Combined contamination of microplastic and antibiotic alters the composition of microbial community and metabolism in wheat and maize rhizosphere soil.

The widespread application of antibiotics and plastic films in agriculture has led to new characteristics of soil pollution. The impacts of combined contamination of microplastics and antibiotics on plant growth and rhizosphere soil bacterial community and metabolisms are still unclear. We conducted a pot experiment to investigate the effects of polyethylene (0.2%) and norfloxacin/doxycycline (5 mg kg-1), as well as the combination of polyethylene and antibiotics, on the growth, rhizosphere soil bacterial community and metabolisms of wheat and maize seedlings. The results showed that combined contamination caused more serious damage to plant growth than individual contamination, and aggravated root oxidative stress responses. The diversity and structure of soil bacterial community were not markedly altered, but the composition of the bacterial community, soil metabolisms and metabolic pathways were altered. The co-occurrence network analysis indicated that combined contamination may inhibit the growth of wheat and maize seedings by simplifying the interrelationships between soil bacteria and metabolites, and altering the relative abundance of specific bacteria genera (e.g. Kosakonia and Sphingomonas) and soil metabolites (including sugars, organic acids and amino acids). The results help to elucidate the potential mechanisms of phytotoxicity of the combination of microplastic and antibiotics.

Robust antibacterial activity of rare-earth ions on planktonic and biofilm bacteria.

Bacterial infections pose a serious threat to human health, with emerging antibiotic resistance, necessitating the development of new antibacterial agents. Cu2+and Ag+are widely recognized antibacterial agents with a low propensity for inducing bacterial resistance; however, their considerable cytotoxicity constrains their clinical applications. Rare-earth ions, owing to their unique electronic layer structure, hold promise as promising alternatives. However, their antibacterial efficacy and biocompatibility relative to conventional antibacterial agents remain underexplored, and the variations in activity across different rare-earth ions remain unclear. Here, we systematically evaluate the antibacterial activity of five rare-earth ions (Yb3+, Gd3+, Sm3+, Tb3+, and La3+) againstStaphylococcus aureusandPseudomonas aeruginosa, benchmarked against well-established antibacterial agents (Cu2+, Ag+) and the antibiotic norfloxacin. Cytotoxicity is also assessed via live/dead staining of fibroblasts after 24 h rare-earth ion exposure. Our findings reveal that rare-earth ions require higher concentrations to match the antibacterial effects of traditional agents but offer the advantage of significantly lower cytotoxicity. In particular, Gd3+demonstrates potent bactericidal efficacy against both planktonic and biofilm bacteria, while maintaining the lowest cytotoxicity toward mammalian cells. Moreover, the tested rare-earth ions also exhibited excellent antifungal activity againstCandida albicans. This study provides a critical empirical framework to guide the selection of rare-earth ions for biomedical applications, offering a strategic direction for the development of novel antimicrobial agents.

Fate and removal of fluoroquinolone antibiotics in mesocosmic wetlands: Impact on wetland performance, resistance genes and microbial communities.

The fate of fluoroquinolone antibiotics norfloxacin and ofloxacin were investigated in mesocosmic wetlands, along with their effects on nutrients removal, antibiotic resistance genes (ARGs) and epiphytic microbial communities on Hydrilla verticillate using bionic plants as control groups. Approximately 99% of norfloxacin and ofloxacin were removed from overlaying water, and H. verticillate inhibited fluoroquinolones accumulation in surface sediments compared to bionic plants. Partial least squares path modeling showed that antibiotics significantly inhibited the nutrient removal capacity (0.55) but had no direct effect on plant physiology. Ofloxacin impaired wetland performance more strongly than norfloxacin and more impacted the primary microbial phyla, whereas substrates played the most decisive role on microbial diversities. High antibiotics concentration shifted the most dominant phyla from Proteobacteria to Bacteroidetes and inhibited the Xenobiotics biodegradation function, contributing to the aggravation in wetland performance. Dechloromonas and Pseudomonas were regarded as the key microorganisms for antibiotics degradation. Co-occurrence network analysis excavated that microorganisms degrade antibiotics mainly through co-metabolism, and more complexity and facilitation/reciprocity between microbes attached to submerged plants compared to bionic plants. Furthermore, environmental factors influenced ARGs mainly by altering the community dynamics of differential bacteria. This study offers new insights into antibiotic removal and regulation of ARGs accumulation in wetlands with submerged macrophyte.

Discovery of indolylacryloyl-derived oxacins as novel potential broad-spectrum antibacterial candidates.

The emergence of serious bacterial resistance towards clinical oxacins poses a considerable threat to global public health, necessitating the development of novel structural antibacterial agents. Seven types of novel indolylacryloyl-derived oxacins (IDOs) were designed and synthesized for the first time from commercial 3,4-difluoroaniline via an eight-step procedure. The synthesized compounds were characterized by modern spectroscopic techniques. All target molecules were evaluated for antimicrobial activities. Most of the prepared IDOs showed a broad antibacterial spectrum and strong activities against the tested strains, especially ethoxycarbonyl IDO 10d (0.25-0.5 µg/mL) and hydroxyethyl IDO 10e (0.25-1 µg/mL) exhibited much superior antibacterial efficacies to reference drug norfloxacin. These highly active IDOs also displayed low hemolysis, cytotoxicity and resistance, as well as rapid bactericidal capacity. Further investigations indicated that ethoxycarbonyl IDO 10d and hydroxyethyl IDO 10e could effectively reduce the exopolysaccharide content and eradicate the formed biofilm, which might delay the development of drug resistance. Preliminary exploration of the antibacterial mechanism revealed that active IDOs could not only destroy membrane integrity, resulting in changes in membrane permeability, but also promote the accumulation of reactive oxygen species, leading to the production of malondialdehyde and decreased bacterial metabolism. Moreover, they exhibited the capability to bind with DNA and DNA gyrase, forming supramolecular complexes through various noncovalent interactions, thereby inhibiting DNA replication and causing bacterial death. All the above results suggested that the newly developed indolylacryloyl-derived oxacins should hold great promise as potential multitargeting broad-spectrum antibacterial candidates to overcome drug resistance.

Hydrazyl hydroxycoumarins as new potential conquerors towards Pseudomonas aeruginosa.

A class of unique hydrazyl hydroxycoumarins (HHs) as novel structural scaffold was developed to combat dreadful bacterial infections. Some HHs could effectively suppress bacterial growth at low concentrations, especially, pyridyl HH 7 exhibited a good inhibition against Pseudomonas aeruginosa 27853 with a low MIC value of 0.5 µg/mL, which was 8-fold more active than norfloxacin. Furthermore, pyridyl HH 7 with low hemolytic activity and low cytotoxicity towards NCM460 cells showed much lower trend to induce the drug-resistant development than norfloxacin. Preliminarily mechanism exploration indicated that pyridyl HH 7 could eradicate the integrity of bacterial membrane, result in the leakage of intracellular proteins, and interact with bacterial DNA gyrase via non-covalent binding, and ADME analysis manifested that compound 7 gave good pharmacokinetic properties. These results suggested that the newly developed hydrazyl hydroxycoumarins as potential multitargeting antibacterial agents should be worthy of further investigation for combating bacterial infection.

Novel aminothiazoximone-corbelled ethoxycarbonylpyrimidones with antibiofilm activity to conquer Gram-negative bacteria through potential multitargeting effects.

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.0066 mmol/L than norfloxacin. It was also revealed that imidazolyl ACE 6c not only possessed inconspicuous hemolytic rate and cytotoxicity, low drug resistance and no risk of penetrating the blood-brain barrier, but also exhibited obvious biofilm inhibition and eradication activities. The preliminary mechanism research suggested that imidazolyl ACE 6c could induce metabolic dysfunction by deactivating lactate dehydrogenase and promote the accumulation of reactive oxygen species to decrease the reduced glutathione and ultimately cause oxidative damage in bacteria. Furthermore, ACE 6c was also found that could insert into DNA to form the supramolecular complex of 6c-DNA and trigger cell death. The multidimensional effect might promote bacterial cell rupture, leading to the leakage of intracellular content. These findings manifested that novel imidazolyl ACE 6c as a potential multitargeting antibacterial agent with potent antibiofilm activity could provide new possibility for the treatment of refractory biofilm-intensified bacterial infections.

Ciprofloxacin and Norfloxacin Hybrid Compounds: Potential Anticancer Agents.

BACKGROUND: The concept of utilizing drug repurposing/repositioning in the development of hybrid molecules is an important strategy in drug discovery. Fluoroquinolones, a class of antibiotics, have been reported to exhibit anticancer activities. Although anticancer drug development is achieving some positive outcomes, there is still a need to develop new and effective anticancer drugs. Some limitations associated with most of the available anticancer drugs are drug resistance and toxicity, poor bio-distribution, poor solubility, and lack of specificity, thereby reducing their therapeutic outcomes. OBJECTIVES: Fluoroquinolones, a known class of antibiotics, have been explored by hybridizing them with other pharmacophores and evaluating their anticancer activity in silico and in vitro. Hence, this review provides an update on new anticancer drugs containing fluoroquinolones moiety, Ciprofloxacin and Norfloxacin between 2020 and 2023, their structural relationship activity, and the future strategies to develop potent chemotherapeutic agents. METHODS: Fluoroquinolones were mostly hybridized via the N-4 of the piperazine ring on position C-7 with known pharmacophores characterized, followed by biological studies to evaluate their anticancer activity. RESULTS: The hybrid molecules displayed promising and interesting anticancer activities. Factors such as the nature of the linker, the presence of electron-withdrawing groups, nature, and position of the substituents influenced the anticancer activity of the synthesized compounds. CONCLUSION: The hybrids were selective towards some cancer cells. However, further in vivo studies are needed to fully understand their mode of action.

Pentafluorosulfanyl-substituted biaryl derivatives as MATE-type transporter inhibitors targeting drug-resistant bacteria.

Multidrug and toxin extrusion (MATE) inhibitors improve the antimicrobial susceptibility of drug-resistant bacteria by preventing the efflux of administered antibiotics. In this study, we optimized the chemical structure of a previously identified bacterial-selective MATE inhibitor 1 (EC50 > 30 µM) to improve its activity further. Compound 1 was divided into three fragments (aromatic part, linker part, and guanidine part), and each part was individually optimized. Compound 31 (EC50 = 1.8 µM), a novel pentafluorosulfanyl-containing molecule synthesized following optimized parts, showed antimicrobial activity against MATE-expressing strains at concentrations lower than conventional inhibitor 1 when co-administrated with norfloxacin. Furthermore, 31 was not cytotoxic at effective concentrations. This suggests that compound 31 can be a promising candidate for combating bacterial infections, particularly those resistant to conventional antibiotics by MATE expression.

Direct Growth Control of Antibiotic-Resistant Bacteria Using Visible-Light-Responsive Novel Photoswitchable Antibiotics.

In addition to the discovery of new (modified) potent antibiotics to combat antibiotic resistance, there is a critical need to develop novel strategies that would restrict their off-target effects and unnecessary exposure to bacteria in our body and environment. We report a set of new photoswitchable arylazopyrazole-modified norfloxacin antibiotics that present a high degree of bidirectional photoisomerization, impressive fatigue resistance and reasonably high cis half-lives. The irradiated isomers of most compounds were found to exhibit nearly equal or higher antibacterial activity than norfloxacin against Gram-positive bacteria. Notably, against norfloxacin-resistant S. aureus bacteria, the visible-light-responsive p-SMe-substituted derivative showed remarkably high antimicrobial potency (MIC of 0.25 µg/mL) in the irradiated state, while the potency was reduced by 24-fold in case of its non-irradiated state. The activity was estimated to be retained for more than 7 hours. This is the first report to demonstrate direct photochemical control of the growth of antibiotic-resistant bacteria and to show the highest activity difference between irradiated and non-irradiated states of a photoswitchable antibiotic. Additionally, both isomers were found to be non-harmful to human cells. Molecular modellings were performed to identify the underlying reason behind the high-affinity binding of the irradiated isomer to topoisomerase IV enzyme.

Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Synthesis, structural, characterization, antibacterial and antibiotic modifying activity, ADMET study, molecular docking and dynamics of chalcone (E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one in strains of Staphylococcus aureus carrying NorA and MepA efflux pumps.

Chalcones have an open chain flavonoid structure that can be obtained from natural sources or by synthesis and are widely distributed in fruits, vegetables, and tea. They have a simple and easy to handle structure due to the α-ß-unsaturated bridge responsible for most biological activities. The facility to synthesize chalcones combined with its efficient in combating serious bacterial infections make these compounds important agents in the fight against microorganisms. In this work, the chalcone (E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (HDZPNB) was characterized by spectroscopy and electronic methods. In addition, microbiological tests were performed to investigate the modulator potential and efflux pump inhibition on S. aureus multi-resistant strains. The modulating effect of HDZPNB chalcone in association with the antibiotic norfloxacin, on the resistance of the S. aureus 1199 strain, resulted in increase the MIC. In addition, when HDZPNB was associated with ethidium bromide (EB), it caused an increase in the MIC value, thus not inhibiting the efflux pump. For the strain of S. aureus 1199B, carrying the NorA pump, the HDZPNB associated with norfloxacin showed no modulatory, and when the chalcone was used in association with EB, it had no inhibitory effect on the efflux pump. For the tested strain of S. aureus K2068, which carries the MepA pump, it can be observed that the chalcone together the antibiotic resulted in an increase the MIC. On the other hand, when chalcone was used in association with EB, it caused a decrease in bromide MIC, equal to the reduction caused by standard inhibitors. Thus, these results indicate that the HDZPNB could also act as an inhibitor of the S. aureus gene overexpressing pump MepA. The molecular docking reveals that chalcone has a good binding energies -7.9 for HDZPNB/MepA complexes, molecular dynamics simulations showed that Chalcone/MetA complexes showed good stability of the structure in an aqueous solution, and ADMET study showed that the chalcone has a good oral bioavailability, high passive permeability, low risk of efflux, low clearance rate and low toxic risk by ingestion. The microbiological tests show that the chalcone can be used as a possible inhibitor of the Mep A efflux pump.Communicated by Ramaswamy H. Sarma.

Sub-inhibitory concentrations of ceftriaxone induce morphological alterations and PIA-independent biofilm formation in Staphylococcus aureus.

The exposure of bacteria to sub-inhibitory concentrations of antibiotics is of biological significance since it can occur in vivo under many circumstances, including low-dose treatment, poor adherence to a regimen, poor drug penetration, drug-drug interactions, and antibiotic resistance of the pathogen. In this study, we investigated the effects of subinhibitory concentrations of four antibiotics: ampicillin, ceftriaxone, gentamicin, and norfloxacin, which are commonly used in clinical settings and on cell morphology and biofilm formation in Staphylococcus aureus as one of the leading causes of nosocomial and biofilm-associated infections. Nine clinical S. aureus biofilm-producing isolates and two known biofilm-producing reference strains, S. aureus ATCC 29213 and S. aureus ATCC 6538, were used in this study. Sub-MICs of beta-lactam antibiotics (ampicillin and ceftriaxone) significantly induced biofilm formation in S. aureus ATCC 29213 and S. aureus ATCC 6538 and in six clinical isolates out of the nine selected isolates when compared with the antibiotic-free control group (P < 0.05), with an approximately 2- to 2.5-fold increase. Gentamicin and norfloxacin induced biofilms in S. aureus ATCC 29213 and S. aureus ATCC 6538, while gentamicin and norfloxacin induced biofilms only in three and two of the nine tested isolates, respectively (P < 0.05). The chemical nature of the biofilm matrix produced by half the MIC of ceftriaxone in the six isolates that showed increased biofilm was all non-polysaccharide in composition (PIA-independent). Gene expression of biofilm-encoding genes atl and sarA in biofilms of the two tested strains (S. aureus ATCC 6538) and clinical strain (S. aureus 16) showed a significant upregulation after exposure to half MIC of ceftriaxone. Additionally, the bacterial cell morphological changes in planktonic cells caused by half MIC of ceftriaxone were evaluated by scanning electron microscopy, which demonstrated a significant cell enlargement when compared with the antibiotic-free control (P < 0.05), and some deformed cells were also noticed. In S. aureus clinical isolates, sub-MICs of ampicillin, ceftriaxone, gentamicin, and norfloxacin may stimulate substantial production of biofilm, which could have important clinical significance and make infection treatment challenges. Further, in vivo research is needed to fully comprehend how sub-MIC of antibiotics can affect biofilm formation in clinical settings. Additionally, more research is required to reveal the clinical implications of the morphological alterations in S. aureus brought on by exposure to ceftriaxone at concentrations below its MIC.

Photoswitchable Antibiotic Hybrids: Spacer Length-Dependent Photochemical Control of Antibacterial Activity.

Photopharmacology holds huge potential for the permanent (long-term) eradication of antibiotic resistance by the application of photoswitchable antibiotics. To construct such antibiotics, various methods have been employed to modify known antibiotics with photoswitches, such that the irradiated state shows activity comparable to or higher than that of the parent antibiotic and that a large activity difference between irradiated and nonirradiated states is achieved. However, most of those methods are ineffective when dealing with more than one drug with dissimilar structures. Here, we have demonstrated a new approach, in which two pharmacophores, one being a photoswitch, are covalently linked via a spacer of variable lengths, leading to a set of azopyrazole-norfloxacin antibiotic hybrids. All compounds showed a high degree of bidirectional photoisomerization, long thermal cis half-lives, and excellent photoresistance. Notably, the hybrid with an optimal four-carbon spacer length enabled the irradiated state to become 12-fold more potent than its nonirradiated state without losing much antimicrobial activity of norfloxacin. Only Gram-positive bacteria were found to be sensitive to this hybrid, and the full antibacterial potency of its irradiated state was found to be retained for nearly 24 h.

Norfloxacin derivatives as DNA gyrase and urease inhibitors: synthesis, biological evaluation and molecular docking.

Background: DNA gyrase and urease enzymes are important targets for the treatment of gastroenteritis, appendicitis, tuberculosis, urinary tract infections and Crohn's disease. Materials & methods: Esterification of norfloxacin was performed to enhance DNA gyrase and urease enzyme inhibition potential. Structure elucidation and chemical characterization were done through spectral (1H NMR, Fourier transform IR, 13C NMR) and carbon, hydrogen, nitrogen and sulfur analysis along with molecular docking. Results & conclusion: The majority of derivatives exhibited significant results but the 3e derivative showed maximum bactericidal, DPPH scavenging (96%), DNA gyrase and urease enzyme inhibitory activity with IC50 of 0.15 ± 0.24 and 1.14 ± 0.11 µM respectively which was further supported by molecular docking studies. So, the active derivatives can serve as a lead compound for the treatment of various pathological conditions.

Benzopyrone-mediated quinolones as potential multitargeting antibacterial agents.

A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5-2 µg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.

Terpene-Functionalized Fluoroquinolones as Potential Antimicrobials: Synthesis and Properties.

This study was the first to synthesize terpene-containing conjugates of fluoroquinolones, ciprofloxacin and norfloxacin, and to evaluate their antibacterial activity against gram-positive methicillin sensitive (MSSA) and methicillin resistant (MRSA) S. aureus, gram-negative P. aeruginosa as well as antifungal activity against C. albicans. The ability of obtained fluoroquinolones to inhibit S. aureus growth was found to depend upon the presence of a linker separating the bulky terpene and fluoroquinolone fragments, and this activity diminished with increasing its length. The highest activity against MSSA was demonstrated by ciprofloxacin derivatives with campholenic (MIC 1 µg/mL) and 2-(isobornan-2-yl-sulfanyl)acetyl (MIC 0.5 µg/mL) substituents. The compound with the last fragment showed high activity against MRSA (MIC 8 µg/mL). The terpene-functionalized norfloxacin derivatives generally proved to be less active than those containing ciprofloxacin fragment. Camphor-10-sulfonylamide derivative with the ciprofloxacin fragment was the only one of all compounds that showed high antifungal activity against C. albicans (8 µg/mL). The study presents data on docking fluoroquinolones to S. aureus DNA gyrase to explain the reasons for manifestation or disappearance of antibacterial activity. The cytotoxicity of fluoroquinolones that showed any antimicrobial activity was investigated against bovine primary lung cells, and they were found to be not toxic in most cases.

An optimized electro-fenton pretreatment for the degradation and mineralization of a mixture of ofloxacin, norfloxacin, and ciprofloxacin.

The electro-Fenton process (EFP) is a powerful advanced oxidation process beneficial to treating recalcitrant contaminants, and there has been a continuing interest in combining this technology to enhance the efficiency of conventional wastewater treatment processes. In this work, an optimized EFP process is performed as pretreatment for the degradation and mineralization of three blank fluoroquinolones (FQs) drugs: ofloxacin (OFL), norfloxacin (NOR), and ciprofloxacin (CIP). The optimization of the experiment was carried out using a Box-Behnken experimental design. Faster and complete degradation of the drugs mixture was achieved in 90 min with 61.12 ± 2.0% of mineralization in 180 min, under the optimized conditions: j = 244.0 mA cm-2, [Fe2+] = 0.31 mM, and [FQs] = 87.0 mg L-1. Furthermore, a low toxicity effluent was obtained in 90 min of the experiment, according to bioassay toxicity with Vibrio fischeri. Five short-chain carboxylic acids, including oxalic, maleic, oxamic, formic, and fumaric acids, were detected and quantified, in addition to F- and NO3- inorganic ions. The inhibition of the reactive oxygen species with scavenger proof was also evaluated in this paper.

Functional Proteomics Analysis of Norfloxacin-Resistant Edwardsiella tarda.

Multidrug-resistant Edwardsiella tarda threatens both sustainable aquaculture and human health, but the control measure is still lacking. In this study, we adopted functional proteomics to investigate the molecular mechanism underlying norfloxacin (NOR) resistance in E. tarda. We found that E. tarda had a global proteomic shift upon acquisition of NOR resistance, featured with increased expression of siderophore biosynthesis and Fe3+-hydroxamate transport. Thus, either inhibition of siderophore biosynthesis with salicyl-AMS or treatment with another antibiotic, kitasamycin (Kit), which was uptake through Fe3+-hydroxamate transport, enhanced NOR killing of NOR-resistant E. tarda both in vivo and in vitro. Moreover, the combination of NOR, salicyl-AMS, and Kit had the highest efficacy in promoting the killing effects of NOR than any drug alone. Such synergistic effect not only confirmed in vitro and in vivo bacterial killing assays but also applicable to other clinic E. tarda isolates. Thus, our data suggest a proteomic-based approach to identify potential targets to enhance antibiotic killing and propose an alternative way to control infection of multidrug-resistant E. tarda.

Thiazolyl hydrazineylidenyl indolones as unique potential multitargeting broad-spectrum antimicrobial agents.

The emergence of pathogenic and drug-resistant microorganisms seriously threatens public safety. This work constructed a unique type of thiazolyl hydrazineylidenyl indolones (THIs) to combat global microbial multidrug-resistance. Bioactive evaluation discovered that some target THIs displayed much superior antimicrobial efficacy than clinical chloromycetin, norfloxacin, cefdinir or fluconazole against the tested strains. Eminently, butyl THI 6c displayed a broad antimicrobial spectrum with low MICs of 0.25-1 µg/mL. The highly active THI 6c not only showed low cytotoxicity and hemolysis, rapidly bactericidal ability, good antibiofilm activity and promising pharmacokinetic properties, but also could significantly impede the development of bacterial resistance. Preliminary exploration of antibacterial mechanism revealed that THI 6c could effectively penetrate the cell membrane of MRSA and embed DNA to form 6c‒DNA supramolecular complex and thus hinder DNA replication. Moreover, THI 6c could reduce cell metabolic activity, which might be attributed to the fact that THI 6c could target the pyruvate kinase of MRSA and interfere with the function of the enzyme. These results provided powerful information for further developing thiazolyl hydrazineylidenyl indolones as new broad-spectrum antimicrobial agents.

Chemical composition and antimicrobial potential of Acrocomia aculeata (Jacq.) Lodd. ex Mart. and Syagrus cearensis Noblick (Arecaceae).

This study aimed to evaluate the antibiotic effects of the fixed oils of Acrocomia aculeata (FOAA) and Syagrus cearenses (FOSC) against the bacterial strains and the fungi strains of the genus Candida spp. The method of serial microdilution using different concentrations was used for measuring the individual biological activity of the fixed oils. The fixed oil of A. aculeata showed the presence of oleic acid (24.36%), while the oil of S. cearensis displayed the content of myristic acid (18.29%), compounds detected in high concentration. The combination FOAA + Norfloxacin, and FOSC + Norfloxacin showed antibacterial activity against E. coli and S. aureus strains, demonstrating possible synergism and potentiation of the antibiotic action against multidrug-resistant strains. The combination FOAA + Fluconazole displayed a significant effect against Candida albicans (IC50 = 15.54), C. krusei (IC50 = 78.58), and C. tropicalis (IC50 = 1588 µg/mL). Regarding FOSC + Fluconazole, it was also observed their combined effect against the strains of C. albicans (IC50 = 3385 µg/mL), C. krusei (IC50 = 26.67 µg/mL), and C. tropicalis (IC50 = 1164 µg/mL). The findings of this study showed a significant synergism for both fixed oils tested when combined with the antibiotic.