Antibacterial, antibiofilm, anti-inflammatory, and wound healing effects of nanoscale multifunctional cationic alternating copolymers.

Infectious diseases caused by new or unknown bacteria and viruses, such as anthrax, cholera, tuberculosis and even COVID-19, are a major threat to humanity. Thus, the development of new synthetic compounds with efficient antimicrobial activity is a necessity. Herein, rationally designed novel multifunctional cationic alternating copolymers were directly synthesized through a step-growth polymerization reaction using a bivalent electrophilic cross-linker containing disulfide bonds and a diamine heterocyclic ring. To optimize the activity of these alternating copolymers, several different diamines and cross-linkers were explored to find the highest antibacterial effects. The synthesized nanopolymers not only displayed good to excellent antibacterial activity as judged by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli, but also reduced the number of biofilm cells even at low concentrations, without killing mammalian cells. Furthermore, in vivo experiments using infected burn wounds in mice demonstrated good antibacterial activity and stimulated wound healing, without causing systemic inflammation. These findings suggest that the multifunctional cationic nanopolymers have potential as a novel antibacterial agent for eradication of multidrug resistant bacterial infections.

Non-Woven Infection Prevention Fabrics Coated with Biobased Cranberry Extracts Inactivate Enveloped Viruses Such as SARS-CoV-2 and Multidrug-Resistant Bacteria.

The Coronavirus Disease (COVID-19) pandemic is demanding the rapid action of the authorities and scientific community in order to find new antimicrobial solutions that could inactivate the pathogen SARS-CoV-2 that causes this disease. Gram-positive bacteria contribute to severe pneumonia associated with COVID-19, and their resistance to antibiotics is exponentially increasing. In this regard, non-woven fabrics are currently used for the fabrication of infection prevention clothing such as face masks, caps, scrubs, shirts, trousers, disposable gowns, overalls, hoods, aprons and shoe covers as protective tools against viral and bacterial infections. However, these non-woven fabrics are made of materials that do not exhibit intrinsic antimicrobial activity. Thus, we have here developed non-woven fabrics with antimicrobial coatings of cranberry extracts capable of inactivating enveloped viruses such as SARS-CoV-2 and the bacteriophage phi 6 (about 99% of viral inactivation in 1 min of viral contact), and two multidrug-resistant bacteria: the methicillin-resistant Staphylococcus aureus and the methicillin-resistant Staphylococcus epidermidis. The morphology, thermal and mechanical properties of the produced filters were characterized by optical and electron microscopy, differential scanning calorimetry, thermogravimetry and dynamic mechanical thermal analysis. The non-toxicity of these advanced technologies was ensured using a Caenorhabditis elegans in vivo model. These results open up a new prevention path using natural and biodegradable compounds for the fabrication of infection prevention clothing in the current COVID-19 pandemic and microbial resistant era.

Protective Face Masks: Current Status and Future Trends.

Management of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has relied in part on the use of personal protective equipment (PPE). Face masks, as a representative example of PPE, have made a particularly significant contribution. However, most commonly used face masks are made of materials lacking inactivation properties against either SARS-CoV-2 or multidrug-resistant bacteria. Therefore, symptomatic and asymptomatic individuals wearing masks can still infect others due to viable microbial loads escaping from the masks. Moreover, microbial contact transmission can occur by touching the mask, and the discarded masks are an increasing source of contaminated biological waste and a serious environmental threat. For this reason, during the current pandemic, many researchers have worked to develop face masks made of advanced materials with intrinsic antimicrobial, self-cleaning, reusable, and/or biodegradable properties, thereby providing extra protection against pathogens in a sustainable manner. To overview this segment of the remarkable efforts against COVID-19, this review describes the different types of commercialized face masks, their main fabrication methods and treatments, and the progress achieved in face mask development.

Antimicrobial susceptibility patterns of respiratory Gram-negative bacterial isolates from COVID-19 patients in Switzerland.

BACKGROUND: Bacterial superinfections associated with COVID-19 are common in ventilated ICU patients and impact morbidity and lethality. However, the contribution of antimicrobial resistance to the manifestation of bacterial infections in these patients has yet to be elucidated. METHODS: We collected 70 Gram-negative bacterial strains, isolated from the lower respiratory tract of ventilated COVID-19 patients in Zurich, Switzerland between March and May 2020. Species identification was performed using MALDI-TOF; antibiotic susceptibility profiles were determined by EUCAST disk diffusion and CLSI broth microdilution assays. Selected Pseudomonas aeruginosa isolates were analyzed by whole-genome sequencing. RESULTS: Pseudomonas aeruginosa (46%) and Enterobacterales (36%) comprised the two largest etiologic groups. Drug resistance in P. aeruginosa isolates was high for piperacillin/tazobactam (65.6%), cefepime (56.3%), ceftazidime (46.9%) and meropenem (50.0%). Enterobacterales isolates showed slightly lower levels of resistance to piperacillin/tazobactam (32%), ceftriaxone (32%), and ceftazidime (36%). All P. aeruginosa isolates and 96% of Enterobacterales isolates were susceptible to aminoglycosides, with apramycin found to provide best-in-class coverage. Genotypic analysis of consecutive P. aeruginosa isolates in one patient revealed a frameshift mutation in the transcriptional regulator nalC that coincided with a phenotypic shift in susceptibility to ß-lactams and quinolones. CONCLUSIONS: Considerable levels of antimicrobial resistance may have contributed to the manifestation of bacterial superinfections in ventilated COVID-19 patients, and may in some cases mandate consecutive adaptation of antibiotic therapy. High susceptibility to amikacin and apramycin suggests that aminoglycosides may remain an effective second-line treatment of ventilator-associated bacterial pneumonia, provided efficacious drug exposure in lungs can be achieved.

Antimicrobial Face Shield: Next Generation of Facial Protective Equipment against SARS-CoV-2 and Multidrug-Resistant Bacteria.

Transparent materials used for facial protection equipment provide protection against microbial infections caused by viruses and bacteria, including multidrug-resistant strains. However, transparent materials used for this type of application are made of materials that do not possess antimicrobial activity. They just avoid direct contact between the person and the biological agent. Therefore, healthy people can become infected through contact of the contaminated material surfaces and this equipment constitute an increasing source of infectious biological waste. Furthermore, infected people can transmit microbial infections easily because the protective equipment do not inactivate the microbial load generated while breathing, sneezing or coughing. In this regard, the goal of this work consisted of fabricating a transparent face shield with intrinsic antimicrobial activity that could provide extra-protection against infectious agents and reduce the generation of infectious waste. Thus, a single-use transparent antimicrobial face shield composed of polyethylene terephthalate and an antimicrobial coating of benzalkonium chloride has been developed for the next generation of facial protective equipment. The antimicrobial coating was analyzed by atomic force microscopy and field emission scanning electron microscopy with elemental analysis. This is the first facial transparent protective material capable of inactivating enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in less than one minute of contact, and the methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. Bacterial infections contribute to severe pneumonia associated with the SARS-CoV-2 infection, and their resistance to antibiotics is increasing. Our extra protective broad-spectrum antimicrobial composite material could also be applied for the fabrication of other facial protective tools such as such as goggles, helmets, plastic masks and space separation screens used for counters or vehicles. This low-cost technology would be very useful to combat the current pandemic and protect health care workers from multidrug-resistant infections in developed and underdeveloped countries.

Antimicrobial Activity of Cyclic-Monomeric and Dimeric Derivatives of the Snail-Derived Peptide Cm-p5 against Viral and Multidrug-Resistant Bacterial Strains.

Cm-p5 is a snail-derived antimicrobial peptide, which demonstrated antifungal activity against the pathogenic strains of Candida albicans. Previously we synthetized a cyclic monomer as well as a parallel and an antiparallel dimer of Cm-p5 with improved antifungal activity. Considering the alarming increase of microbial resistance to conventional antibiotics, here we evaluated the antimicrobial activity of these derivatives against multiresistant and problematic bacteria and against important viral agents. The three peptides showed a moderate activity against Pseudomonas aeruginosa, Klebsiella pneumoniae Extended Spectrum ß-Lactamase (ESBL), and Streptococcus agalactiae, with MIC values > 100 µg/mL. They exerted a considerable activity with MIC values between 25-50 µg/mL against Acinetobacter baumanii and Enterococcus faecium. In addition, the two dimers showed a moderate activity against Pseudomonas aeruginosa PA14. The three Cm-p5 derivatives inhibited a virulent extracellular strain of Mycobacterium tuberculosis, in a dose-dependent manner. Moreover, they inhibited Herpes Simplex Virus 2 (HSV-2) infection in a concentration-dependent manner, but had no effect on infection by the Zika Virus (ZIKV) or pseudoparticles of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). At concentrations of >100 µg/mL, the three new Cm-p5 derivatives showed toxicity on different eukaryotic cells tested. Considering a certain cell toxicity but a potential interesting activity against the multiresistant strains of bacteria and HSV-2, our compounds require future structural optimization.

Clinical Perspectives of Multiple and Extensively Drug-Resistant Typhoid; result from a tertiary care hospital from Pakistan.

INTRODUCTION: Typhoid fever remains a problem in developing countries, including Pakistan. The emergence of multidrug-resistant and, since 2016, of extensively drug-resistant cases is a continuous challenge for health care workers. The COVID-19 pandemic is making management more difficult. METHODOLOGY: In the present study, a total of 52 confirmed cases of typhoid have been studied during 2019. Detailed clinical features, complications and, lab findings were studied. Typhoid culture and sensitivity were recorded and patients were treated accordingly. Patients were asked about risk factors to aim at informing prevention. RESULTS: Out of the 52 having blood culture positive for Salmonella Typhi 47 (90.4%) and Salmonella Paratyphi 5 (9.6%), 4 (7.7%) were sensitive to first-line (Non-resistant), 11 (21.2%) MDR and 37 (71.2%) patient were XDR. One case was resistant to azithromycin. Nausea, vomiting or, abdominal pain was present in 12 (23%), abdominal distension present in 9 (17.3%), abdominal tenderness in 8 (15.4%), hepatomegaly in 10 (19.2%) and, splenomegaly in 22 (42.3%).There were ultrasound abnormalities in 58% of patients and GI complications in 19% of patients. No significant difference was found in clinical findings and complications between resistant and non-resistant cases. Only 23-27% of patients were aware of typhoid prevention and vaccination measures. CONCLUSIONS: The increasing prevalence of resistance and higher degree of complications seen in typhoid fever raises the concern further about prevention and effective infection management in the community as well as clinical settings. Moreover, judicial use of antibiotics is much needed in developing countries like Pakistan.

MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections.

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.

Antibiotic Potentiation of Natural Products: A Promising Target to Fight Pathogenic Bacteria.

Pathogenic microorganisms should be considered as the number one foe of human, as witnessed by recent outbreaks of coronavirus disease (COVID-19) and with bacteria no longer sensitive to existing antibiotics. The resistance of pathogenic bacteria and deaths attributable to bacterial infections is increasing exponentially. Bacteria used different mechanisms to counterattack to existing antibiotics, namely (i) enzymatic inhibition, (ii) penicillin-binding protein modification, (iii) porin mutations, (iv) efflux pumps and (v) molecular modifications of antibiotic targets. Developing new antibiotics would be time-consuming to address such a situation, thus one of the promising approaches is by potentiating existing antibiotics. Plants used synergism to naturally defend and protect themselves from microbes. Using the same strategy, several studies have shown that the combinations of natural products and antibiotics could effectively prolong the lifespan of existing antibiotics and minimize the impact and emergence of antibiotic resistance. Combining essential oils constituents, namely uvaol, ferruginol, farnesol and carvacrol, with antibiotics, have proved to be efficient efflux pump inhibitors. Plant-derived compounds such as gallic acid and tannic acid are effective potentiators of various antibiotics, including novobiocin, chlorobiocin, coumermycin, fusidic acid, and rifampicin, resulting in a 4-fold increase in the potencies of these antibiotics. Several lines of research, as discussed in this review, have demonstrated the effectiveness of natural products in potentiating existing antibiotics. For this reason, the search for more efficient combinations should be an ongoing process with the aim to extend the life of the ones that we have and may preserve the life for the ones that are yet to come.