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1.
J Antibiot (Tokyo) ; 75(6): 321-332, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1878523

ABSTRACT

Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases - cathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with KD value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.


Subject(s)
COVID-19 , Staphylococcal Infections , Aminoacyltransferases , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Biofilms , Cysteine Endopeptidases , Humans , Microbial Sensitivity Tests , RNA, Viral/pharmacology , SARS-CoV-2 , Staphylococcus aureus
2.
J Infect Chemother ; 28(7): 978-981, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1851523

ABSTRACT

Netherton's syndrome, a rare congenital disorder, is clinically characterized by chronic dermatologic disorders such as ichthyosiform erythroderma and ichthyosis linearis circumflexa. Curable treatment is yet to be established, and corticosteroid ointment is required to maintain good dermatological condition. Because of the permanent skin barrier impairment, patients with Netherton's syndrome are considered to be vulnerable to cutaneous infections. However, its clinical characteristics are yet to be elucidated due to the limited number of reported cases. Herein, we describe the clinical course of a patient who developed persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A 19-year-old Japanese woman who had been diagnosed with Netherton's syndrome in her infancy and had been applying topical corticosteroid agents all over her body since her then, was referred to our hospital because of persistent MRSA bacteremia and secondary adrenal insufficiency. The patient was diagnosed with a central line-associated bloodstream infection and was appropriately treated with antibiotics and corticosteroid therapies. We assume that the damaged skin barrier due to the congenital dermatological disorder causes a disruption in the normal bacterial flora of the skin, leading to the invasion of harmful bacteria, such as S. aureus. In addition, internal (humoral immunodeficiency by decreased antibody against bacterial polysaccharide antigens) and external (prolonged and systemic use of corticosteroid ointment) factors bring about an immunodeficiency state in such patients. We highlight that in the absence of radical treatment, clinicians need to recognize that patients with Netherton's syndrome are vulnerable to bacterial infections owing to the mixture of immunosuppressive factors.


Subject(s)
Bacteremia , Methicillin-Resistant Staphylococcus aureus , Adult , Bacteremia/drug therapy , Female , Humans , Ointments , Staphylococcus aureus , Syndrome , Young Adult
3.
Int J Mol Sci ; 23(9)2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1847340

ABSTRACT

In this study, humidified air dielectric barrier discharge (DBD) plasma was used to inactivate Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and bacteriophages in biofilms containing DNA, NaCl, carbohydrates, and proteins. The humidified DBD plasma was very effective in the inactivation of microbes in the (≤1.0 µm) biofilms. The number of surviving E. coli, S. aureus, and bacteriophages in the biofilms was strongly dependent on the constituent and thickness of the biofilms and was greatly reduced when the plasma treatment time increased from 5 s to 150 s. Our analysis shows that the UV irradiation was not responsible for the inactivation of microbes in biofilms. The short-lived RONS generated in the humidified air DBD plasma were not directly involved in the inactivation process; however, they recombined or reacted with other species to generate the long-lived RONS. Long-lived RONS diffused into the biofilms to generate very active species, such as ONOOH and OH. This study indicates that the geminated NO2 and OH pair formed due to the homolysis of ONOOH can cause the synergistic oxidation of various organic molecules in the aqueous solution. Proteins in the biofilm were highly resistant to the inactivation of microbes in biofilms, which is presumably due to the existence of the unstable functional groups in the proteins. The unsaturated fatty acids, cysteine-rich proteins, and sulfur-methyl thioether groups in the proteins were easily oxidized by the geminated NO2 and OH pair.


Subject(s)
Bacteriophages , Escherichia coli Infections , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Biofilms , Escherichia coli/physiology , Humans , Nitrogen Dioxide , Staphylococcus aureus/physiology
4.
Drugs ; 82(5): 533-557, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1827389

ABSTRACT

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.


Subject(s)
Bacteriuria , Methicillin-Resistant Staphylococcus aureus , Prodrugs , Urinary Tract Infections , Adenosine Monophosphate/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteriuria/chemically induced , Bacteriuria/drug therapy , Carbapenems/pharmacology , Cephalosporins/pharmacology , Ciprofloxacin/pharmacology , Ertapenem , Escherichia coli , Female , Fluoroquinolones/pharmacology , Gram-Negative Bacteria , Guinea Pigs , Humans , Imipenem/pharmacology , Lactams , Male , Membrane Proteins/pharmacology , Meropenem/pharmacology , Mice , Probenecid/pharmacology , Prodrugs/pharmacology , Staphylococcus aureus , Urinary Tract Infections/drug therapy , beta-Lactamases/pharmacology
5.
Int J Biol Macromol ; 207: 100-109, 2022 May 15.
Article in English | MEDLINE | ID: covidwho-1814498

ABSTRACT

In this study, Cu/Zn galvanic electrodes were sputtered on the two surfaces of hydrophilic cotton fiber nonwovens (Cotton) to prepare hydro electroactive Cu/Cotton/Zn composites. When the Cu/Cotton/Zn was used as a functional layer in the face mask, the Cu/Zn galvanic electrodes can be spontaneously activated by water vapor molecules exhaled by the human body and generate galvanic current. Based on this, the hydro electroactive Cu/Cotton/Zn demonstrated excellent antibacterial activity against Escherichia coli and Staphylococcus aureus and could deactivate Enterovirus 71 (EV71) virions transmitted through the respiratory tract by 97.72% after 15 min of contact. Moreover, the Cu/Cotton/Zn did not affect the particle filtration efficiency and breathability of the face mask's polypropylene (PP) melt-blown layer. Furthermore, the cytotoxicity assessment of Cu/Cotton/Zn showed no cytotoxicity, indicating good biological security. Overall, the Cu/Cotton/Zn may provide a new approach to increase the antibacterial and antiviral performance of current personnel protective equipment on the market.


Subject(s)
Antiviral Agents , Cotton Fiber , Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , Escherichia coli , Humans , Staphylococcus aureus , Zinc
6.
Int J Mol Sci ; 23(8)2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1809940

ABSTRACT

Polymer microgels, including those based on interpenetrating networks (IPNs), are currently vastly studied, and their practical applications are a matter of thriving research. In this work, we show the perspective for the use of polyelectrolyte IPN microgels either as scavengers or carriers of antiseptic substances. Here, we report that poly-N-isopropylacrylamide/polyacrylic acid IPN microgels can efficiently absorb the common bactericidal and virucidal compound benzalkonium chloride. The particles can form a stable aqueous colloidal suspension or be used as building blocks for soft free-standing films. Both materials showed antiseptic efficacy on the examples of Bacillus subtilis and S. aureus, which was approximately equal to the commercial antibiotic. Such polymer biocides can be used as liquid disinfectants, stable surface coatings, or parts of biomedical devices and can enhance the versatility of the possible practical applications of polymer microgels.


Subject(s)
Anti-Infective Agents, Local , Microgels , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents, Local/pharmacology , Benzalkonium Compounds , Polymers , Staphylococcus aureus
7.
Int J Environ Res Public Health ; 19(8)2022 04 17.
Article in English | MEDLINE | ID: covidwho-1809883

ABSTRACT

Healthcare-related infections are sustained by various bacteria and fungi. In recent years, various technologies have emerged for the sanitation of healthcare-related environments. This study evaluated the effectiveness of a no-touch disinfection system that aerosolizes 5% hydrogen peroxide and 10% ethyl alcohol. After selecting an environment, the Total Bacterial Count and the Total Fungal Count in the air and on a surface of the room were determined to evaluate the effectiveness of the aerosolization system. In addition, sterile stainless-steel plates inoculated with S. aureus, P. aeruginosa, and Aspergillus spp. isolated from hospitalized patients and reference strains were used to evaluate the effectiveness of the system. For each organism, three plates were used: A (cleaned), B (not cleaned), and C (control). The A plates were treated with non-ionic surfactant and the aerosolization system, the B plates were subjected to the aerosolization system, and the plates C were positioned outside the room that was sanitized. Following sanitization, air and surface sampling was conducted, after which, swabs were processed for bacterial and fungal enumeration. The results showed that the air sanitization system had good efficacy for both bacteria and fungi in the air and on stainless-steel plates, particularly for the A plates.


Subject(s)
Disinfectants , Disinfection , Aerosols , Bacteria , Delivery of Health Care , Disinfection/methods , Ethanol , Humans , Hydrogen Peroxide , Pseudomonas aeruginosa , Stainless Steel , Staphylococcus aureus
8.
Int J Environ Res Public Health ; 19(8)2022 04 16.
Article in English | MEDLINE | ID: covidwho-1809881

ABSTRACT

In sub-Saharan Africa, there is limited information about the use of microbiology laboratory services in patients with suspected urinary tract infections (UTIs). This cross-sectional study assessed the requests for urine culture in patients with suspected UTI in two tertiary (maternal and paediatric) hospitals-Freetown and Sierra Leone, during May 2017-May 2021-and determined antimicrobial resistance (AMR) patterns among bacterial isolates. One laboratory served the two hospitals, with its electronic database used to extract information. Overall, there were 980 patients, of whom 168 (17%) had cultures requested and performed. Of these, 75 (45%) were culture positive. During 2017-2019, there were 930 patients, of whom 156 (17%) had cultures performed. During 2020-2021, when services were disrupted by the COVID-19 pandemic, there were 50 patients, of whom 12 (24%) had cultures performed. The four commonest isolates were Escherichia coli (36), Klebsiella pneumoniae (10), Staphylococcus aureus (9), and Pseudomonas spp. (6). There were high levels of AMR, especially for trimethoprim-sulfamethoxazole (47%), nalidixic acid (44%), nitrofurantoin (32%) and cefotaxime (36%). Overall, 41 (55%) bacterial isolates showed multidrug resistance, especially E. coli (58%), Pseudomonas spp. (50%), and S. aureus (44%). These findings support the need for better utilization of clinical microbiology services to guide antibiotic stewardship and monitoring of trends in resistance patterns.


Subject(s)
COVID-19 , Urinary Tract Infections , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Child , Cross-Sectional Studies , Drug Resistance, Bacterial , Drug Resistance, Multiple , Escherichia coli , Female , Humans , Male , Microbial Sensitivity Tests , Pandemics , Sierra Leone/epidemiology , Staphylococcus aureus , Tertiary Care Centers , Urinary Tract Infections/drug therapy , Urinary Tract Infections/epidemiology , Urinary Tract Infections/microbiology
9.
ACS Chem Biol ; 17(5): 1239-1248, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-1805550

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic-resistant bacterial infections acquired during hospital stays have increased. Antibiotic adjuvants are a key strategy to combat these bacteria. We have evaluated several small molecule antibiotic adjuvants that have strong potentiation with ß-lactam antibiotics and are likely inhibiting a master regulatory kinase, Stk1. Here, we investigated how the lead adjuvant (compound 8) exerts its effects in a more comprehensive manner. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with oxacillin and the adjuvant. Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up- and downregulated, respectively, in response to cotreatment. Gene ontology categories and biochemical pathways that were significantly enriched with downregulated genes involved carbohydrate utilization, such as the citrate cycle and the phosphotransferase system. One of the most populated pathways was S. aureus infection. Results from an interaction network constructed with affected gene products supported the hypothesis that Stk1 is a target of compound 8. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect due to Stk1 inhibition. These results point to this antibiotic adjuvant having potential broad therapeutic use in combatting MRSA.


Subject(s)
COVID-19 , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Carbazoles/pharmacology , Humans , Methicillin-Resistant Staphylococcus aureus/genetics , Microbial Sensitivity Tests , Pandemics , Staphylococcus aureus , Transcriptome
10.
BMJ Open ; 12(3): e056706, 2022 03 10.
Article in English | MEDLINE | ID: covidwho-1794496

ABSTRACT

OBJECTIVES: To determine the causes of lobar pneumonia in rural Gambia. DESIGN AND SETTING: Population-based pneumonia surveillance at seven peripheral health facilities and two regional hospitals in rural Gambia. 7-valent pneumococcal conjugate vaccine (PCV7) was introduced routinely in August 2009 and replaced by PCV13 from May 2011. METHODS: Prospective pneumonia surveillance was undertaken among all ages with referral of suspected pneumonia cases to the regional hospitals. Blood culture and chest radiographs were performed routinely while lung or pleural aspirates were collected from selected, clinically stable patients with pleural effusion on radiograph and/or large, dense, peripheral consolidation. We used conventional microbiology, and from 8 April 2011 to 17 July 2012, used a multiplex PCR assay on lung and pleural aspirates. We calculated proportions with pathogens, associations between coinfecting pathogens and PCV effectiveness. PARTICIPANTS: 2550 patients were admitted with clinical pneumonia; 741 with lobar pneumonia or pleural effusion. We performed 181 lung or pleural aspirates and multiplex PCR on 156 lung and 4 pleural aspirates. RESULTS: Pathogens were detected in 116/160 specimens, the most common being Streptococcus pneumoniae(n=68), Staphylococcus aureus (n=26) and Haemophilus influenzae type b (n=11). Bacteria (n=97) were more common than viruses (n=49). Common viruses were bocavirus (n=11) and influenza (n=11). Coinfections were frequent (n=55). Moraxella catarrhalis was detected in eight patients and in every case there was coinfection with S. pneumoniae. The odds ratio of vaccine-type pneumococcal pneumonia in patients with two or three compared with zero doses of PCV was 0.17 (95% CI 0.06 to 0.51). CONCLUSIONS: Lobar pneumonia in rural Gambia was caused primarily by bacteria, particularly S. pneumoniae and S. aureus. Coinfection was common and M. catarrhalis always coinfected with S. pneumoniae. PCV was highly efficacious against vaccine-type pneumococcal pneumonia.


Subject(s)
Coinfection , Pleural Effusion , Pneumococcal Infections , Pneumonia, Pneumococcal , Viruses , Coinfection/epidemiology , Gambia/epidemiology , Humans , Infant , Lung , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/therapeutic use , Pneumonia, Pneumococcal/diagnosis , Pneumonia, Pneumococcal/epidemiology , Pneumonia, Pneumococcal/prevention & control , Prospective Studies , Staphylococcus aureus , Streptococcus pneumoniae/genetics
11.
Molecules ; 27(7)2022 Mar 24.
Article in English | MEDLINE | ID: covidwho-1785835

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have a substantial impact on health concerns. The current worldwide prevalence of MRSA infections highlights the need for long-lasting preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine candidates and drug target proteins against the 16 strains of MRSA using reverse vaccinology and subtractive genomics approaches. Using the reverse vaccinology approach, 4 putative antigenic proteins were identified; among these, PrsA and EssA proteins were found to be more promising vaccine candidates. We applied a molecular docking approach of selected 8 drug target proteins with the drug-like molecules, revealing that the ZINC4235426 as potential drug molecule with favorable interactions with the target active site residues of 5 drug target proteins viz., biotin protein ligase, HPr kinase/phosphorylase, thymidylate kinase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-L-lysine ligase, and pantothenate synthetase. Thus, the identified proteins can be used for further rational drug or vaccine design to identify novel therapeutic agents for the treatment of multidrug-resistant staphylococcal infection.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Vaccines , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Genomics , Humans , Ligases , Methicillin-Resistant Staphylococcus aureus/genetics , Molecular Docking Simulation , Staphylococcal Infections/prevention & control , Staphylococcus aureus , Vaccinology
12.
ACS Chem Biol ; 17(5): 1184-1196, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-1783934

ABSTRACT

Vaccine scaffolds and carrier proteins increase the immunogenicity of subunit vaccines. Here, we developed, characterized, and demonstrated the efficacy of a novel microparticle vaccine scaffold comprised of bacterial peptidoglycan (PGN), isolated as an entire sacculi. The PGN microparticles contain bio-orthogonal chemical handles allowing for site-specific attachment of immunogens. We first evaluated the purification, integrity, and immunogenicity of PGN microparticles derived from a variety of bacterial species. We then optimized PGN microparticle modification conditions; Staphylococcus aureus PGN microparticles containing azido-d-alanine yielded robust conjugation to immunogens. We then demonstrated that this vaccine scaffold elicits comparable immunostimulation to the conventional carrier protein, keyhole limpet hemocyanin (KLH). We further modified the S. aureus PGN microparticle to contain the SARS-CoV-2 receptor-binding domain (RBD)─this conjugate vaccine elicited neutralizing antibody titers comparable to those elicited by the KLH-conjugated RBD. Collectively, these findings suggest that chemically modified bacterial PGN microparticles are a conjugatable and biodegradable microparticle scaffold capable of eliciting a robust immune response toward an antigen of interest.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Humans , Peptidoglycan , Staphylococcus aureus , Vaccines, Conjugate , Vaccines, Subunit
13.
BMC Infect Dis ; 22(1): 330, 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1775313

ABSTRACT

BACKGROUND: Respiratory infections among children, particularly community-acquired pneumonia (CAP), is a major disease with a high frequency among outpatient and inpatient visits. The causes of CAP vary depending on individual susceptibility, the epidemiological characteristics of the community, and the season. We performed this study to establish a nationwide surveillance network system and identify the causative agents for CAP and antibiotic resistance in Korean children with CAP. METHODS: The monitoring network was composed of 28 secondary and tertiary medical institutions. Upper and lower respiratory samples were assayed using a culture or polymerase chain reaction (PCR) from August 2018 to May 2020. RESULTS: A total of 1023 cases were registered in patients with CAP, and PCR of atypical pneumonia pathogens revealed 422 cases of M. pneumoniae (41.3%). Respiratory viruses showed a positivity rate of 65.7% by multiplex PCR test, and human rhinovirus was the most common virus, with 312 cases (30.5%). Two hundred sixty four cases (25.8%) were isolated by culture, including 131 cases of S. aureus (12.8%), 92 cases of S. pneumoniae (9%), and 20 cases of H. influenzae (2%). The cultured, isolated bacteria may be colonized pathogen. The proportion of co-detection was 49.2%. The rate of antibiotic resistance showed similar results as previous reports. CONCLUSIONS: This study will identify the pathogens that cause respiratory infections and analyze the current status of antibiotic resistance to provide scientific evidence for management policies of domestic respiratory infections. Additionally, in preparation for new epidemics, including COVID-19, monitoring respiratory infections in children and adolescents has become more important, and research on this topic should be continuously conducted in the future.


Subject(s)
COVID-19 , Community-Acquired Infections , Pneumonia, Mycoplasma , Adolescent , Child , Community-Acquired Infections/microbiology , Humans , Multiplex Polymerase Chain Reaction/methods , Staphylococcus aureus
14.
Sci Rep ; 12(1): 5468, 2022 03 31.
Article in English | MEDLINE | ID: covidwho-1768860

ABSTRACT

This study investigated the performance of 24 commercial disinfectants present on the market during last year according to the manufacturer's instructions. Recently, national and international organizations of public health performed studies on disinfection products due to the increasing awareness of the potential and growing risks on human health, such as skin damage and reactions in the mucosal lining, especially for the healthcare workers in their frequent daily use. However, there are many limitations in the common cleaning/disinfection products on market as in the selection of effective disinfectants to decontaminate inanimate surfaces. We analyzed the disinfection power of hydrogen peroxide, quaternary ammonium compounds, alcohols, phenols and aldehydes used as active principles according to international guidelines. The antimicrobial properties were assessed by broth microdilution, and antibiofilm properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus); their virucidal efficacy was tested against Herpes simplex virus type 1 (HSV-1) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The quaternary ammonium compounds demonstrated better efficacy than others and in some cases ready to use products had also virucidal and antimicrobial activities after dilution at 0.125%. The scientific evidence indicates that many commercial products are used at high concentrations and high doses and this could have deleterious effects both on human health and the environment. A lower concentration of active ingredients would avoid the excessive release of chemicals into the environment and improve skin tolerance, ensuring the health and safety protection of workers, including the healthcare operators at their workplace.


Subject(s)
COVID-19 , Disinfectants , COVID-19/prevention & control , Disinfectants/pharmacology , Escherichia coli , Humans , Pandemics/prevention & control , SARS-CoV-2 , Staphylococcus aureus , Workplace
15.
J Med Case Rep ; 16(1): 140, 2022 Mar 28.
Article in English | MEDLINE | ID: covidwho-1765465

ABSTRACT

BACKGROUND: Neonates with severe acute respiratory syndrome coronavirus 2 infection are usually asymptomatic or have mild to moderate symptoms. Acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus 2 with respiratory insufficiency is rare. Therefore, information about the best intensive care strategy for neonates requiring mechanical ventilation is lacking. We report a neonatal case of severe acute respiratory distress syndrome, probably due to vertical transmission of severe acute respiratory syndrome coronavirus 2, complicated by Staphylococcus aureus sepsis. We aim to inform pediatric providers on the clinical course and acute management considerations in coronavirus disease-related neonatal acute respiratory distress syndrome. CASE PRESENTATION: A late preterm (gestational age 36 0/7 weeks) Caucasian girl was born from a severe acute respiratory syndrome coronavirus 2-positive mother and tested positive for severe acute respiratory syndrome coronavirus 2 at 19 hours after birth. She developed acute respiratory distress syndrome requiring intensive care admission and mechanical ventilation. The clinical course was complicated by S. aureus pneumonia and bacteremia. Multimodal management included well-established interventions for respiratory distress syndrome such as surfactant therapy, high-frequency oscillatory ventilation, and inhaled nitric oxide, combined with therapies extrapolated from adult care for severe acute respiratory syndrome coronavirus 2 patients such as dexamethasone, coronavirus disease 2019-specific immunoglobins, and prophylactic low-molecular-weight heparin. The neonate was successfully weaned from the ventilator and improved clinically. CONCLUSION: This case shows a rare but serious neonatal severe acute respiratory syndrome coronavirus 2 infection, leading to severe acute respiratory distress syndrome. Because of limited therapy guidelines for neonates, we suggest multimodal management with awareness of the possibility of S. aureus coinfection, to treat this age group successful.


Subject(s)
COVID-19 , Respiratory Distress Syndrome, Newborn , Respiratory Insufficiency , COVID-19/complications , COVID-19/therapy , Child , Female , Humans , Infant, Newborn , Respiratory Distress Syndrome, Newborn/etiology , Respiratory Distress Syndrome, Newborn/therapy , SARS-CoV-2 , Staphylococcus aureus
16.
Int J Mol Sci ; 23(6)2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1760652

ABSTRACT

The presence of co-infections or superinfections with bacterial pathogens in COVID-19 patients is associated with poor outcomes, including increased morbidity and mortality. We hypothesized that SARS-CoV-2 and its components interact with the biofilms generated by commensal bacteria, which may contribute to co-infections. This study employed crystal violet staining and particle-tracking microrheology to characterize the formation of biofilms by Streptococcus pneumoniae and Staphylococcus aureus that commonly cause secondary bacterial pneumonia. Microrheology analyses suggested that these biofilms were inhomogeneous soft solids, consistent with their dynamic characteristics. Biofilm formation by both bacteria was significantly inhibited by co-incubation with recombinant SARS-CoV-2 spike S1 subunit and both S1 + S2 subunits, but not with S2 extracellular domain nor nucleocapsid protein. Addition of spike S1 and S2 antibodies to spike protein could partially restore bacterial biofilm production. Furthermore, biofilm formation in vitro was also compromised by live murine hepatitis virus, a related beta-coronavirus. Supporting data from LC-MS-based proteomics of spike-biofilm interactions revealed differential expression of proteins involved in quorum sensing and biofilm maturation, such as the AI-2E family transporter and LuxS, a key enzyme for AI-2 biosynthesis. Our findings suggest that these opportunistic pathogens may egress from biofilms to resume a more virulent planktonic lifestyle during coronavirus infections. The dispersion of pathogens from biofilms may culminate in potentially severe secondary infections with poor prognosis. Further detailed investigations are warranted to establish bacterial biofilms as risk factors for secondary pneumonia in COVID-19 patients.


Subject(s)
Antibiosis , Biofilms , Coronavirus/physiology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Staphylococcus aureus/physiology , Streptococcus pneumoniae/physiology , Animals , Coinfection , Gene Expression Regulation, Bacterial , Humans , Mice , Microbial Interactions , Serogroup , Staphylococcus aureus/classification , Streptococcus pneumoniae/classification
17.
Pediatr Infect Dis J ; 41(4): e142-e145, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1752202

ABSTRACT

We reviewed all cases of Panton-Valentine leukocidin-producing Staphylococcus aureus (PVL-SA) bacteremia in Danish children between 2016 and 2021. We found 2 fatal cases with preceding viral prodrome due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the usual benign course of SARS-CoV-2 infection in children, awareness of possible superinfection with PVL-SA in a child with rapid deterioration is crucial to ensure adequate treatment, including antimicrobial drugs with antitoxin effect.


Subject(s)
Bacteremia , Bacterial Toxins/biosynthesis , COVID-19/complications , Exotoxins/biosynthesis , Leukocidins/biosynthesis , SARS-CoV-2 , Staphylococcal Infections/etiology , Staphylococcal Infections/mortality , Staphylococcus aureus/genetics , Adolescent , COVID-19/virology , Child , Child, Preschool , Coinfection , Comorbidity , Denmark/epidemiology , Female , Humans , Infant , Male , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/metabolism , Public Health Surveillance , Severity of Illness Index , Staphylococcal Infections/diagnosis , Staphylococcal Infections/therapy , Staphylococcus aureus/drug effects , Staphylococcus aureus/metabolism
18.
BMJ Case Rep ; 15(3)2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1723594

ABSTRACT

A man fully mRNA-vaccinated against COVID-19 presented to our hospital with an acute febrile illness, respiratory symptoms and a positive test for SARS-CoV-2. He was later found early into hospitalisation to have two morbid bacterial co-infections: Legionella pneumophila serogroup 1 and methicillin-resistant Staphylococcus aureus (MRSA). Although this patient was initially admitted for COVID-19 management, his initial presentation was remarkable for lobar pneumonia, hyponatraemia and rhabdomyolysis more compatible with Legionnaire's disease than severe COVID-19. On discovery of MRSA pneumonia as a second bacterial infection, immunosuppressive COVID-19 therapies were discontinued and targeted antibiotics towards both bacterial co-infections were initiated. The patient's successful recovery highlighted the need to have high suspicion for bacterial co-infections in patients presenting with community-acquired pneumonia and a positive SARS-CoV-2 test, as patients with serious bacterial co-infections may have worse outcomes with use of immunosuppressive COVID-19 therapies.


Subject(s)
COVID-19 , Coinfection , Community-Acquired Infections , Legionella pneumophila , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Anti-Bacterial Agents/therapeutic use , COVID-19/complications , Coinfection/diagnosis , Community-Acquired Infections/microbiology , Humans , Male , SARS-CoV-2 , Staphylococcal Infections/complications , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Staphylococcus aureus
19.
Curr Opin Infect Dis ; 35(2): 149-162, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1672443

ABSTRACT

PURPOSE OF REVIEW: Some patients with coronavirus disease 2019 (COVID-19) may develop pulmonary bacterial coinfection or superinfection, that could unfavorably impact their prognosis. RECENT FINDINGS: The exact burden of methicillin-resistant Staphylococcus aureus (MRSA) lung infection in peculiar populations such as patients with COVID-19 remains somewhat elusive, possibly because of wide heterogeneity in methods and endpoints across studies. SUMMARY: There was important heterogeneity in the retrieved literature on the epidemiology of MRSA lung infection in patients with COVID-19, both when considering all other bacteria as the denominator (relative prevalence ranging from 2% to 29%) and when considering only S. aureus as the denominator (relative prevalence ranging from 11% to 65%). Overall, MRSA is among the most frequent causative agents of pulmonary infection in patients with COVID-19. Improving our ability to rapidly reach etiological diagnosis of bacterial lung infection in COVID-19 patients remains fundamental if we are to improve the rates of appropriate antibiotic therapy in patients with COVID-19 and concomitant/superimposed MRSA infection, at the same time avoiding antibiotic overuse in line with antimicrobial stewardship principles.


Subject(s)
COVID-19 , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Anti-Bacterial Agents/therapeutic use , COVID-19/complications , Humans , Lung , SARS-CoV-2 , Staphylococcal Infections/complications , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcus aureus
20.
Mar Drugs ; 20(1)2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1667236

ABSTRACT

The underexplored biodiversity of seaweeds has recently drawn great attention from researchers to find the bioactive compounds that might contribute to the growth of the blue economy. In this study, we aimed to explore the effect of seasonal growth (from May to September) on the in vitro antioxidant (FRAP, DPPH, and ORAC) and antimicrobial effects (MIC and MBC) of Cystoseira compressa collected in the Central Adriatic Sea. Algal compounds were analyzed by UPLC-PDA-ESI-QTOF, and TPC and TTC were determined. Fatty acids, among which oleic acid, palmitoleic acid, and palmitic acid were the dominant compounds in samples. The highest TPC, TTC and FRAP were obtained for June extract, 83.4 ± 4.0 mg GAE/g, 8.8 ± 0.8 mg CE/g and 2.7 ± 0.1 mM TE, respectively. The highest ORAC value of 72.1 ± 1.2 µM TE was obtained for the August samples, and all samples showed extremely high free radical scavenging activity and DPPH inhibition (>80%). The MIC and MBC results showed the best antibacterial activity for the June, July and August samples, when sea temperature was the highest, against Listeria monocytogenes, Staphylococcus aureus, and Salmonella enteritidis. The results show C. compressa as a potential species for the industrial production of nutraceuticals or functional food ingredients.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antioxidants/pharmacology , Plant Extracts/pharmacology , Seaweed , Animals , Anti-Bacterial Agents/chemistry , Antioxidants/chemistry , Aquatic Organisms , Biphenyl Compounds , Mediterranean Sea , Microbial Sensitivity Tests , Picrates , Plant Extracts/chemistry , Salmonella enteritidis/drug effects , Seasons , Staphylococcus aureus/drug effects
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