Important Class Of Antibiotics Research Articles

Temporal trends in antimicrobial resistance of medically important pathogens on Curaçao

BackgroundThe Caribbean lacks recent comprehensive antimicrobial resistance data to inform clinicians and decision-makers. This study aims to provide a snapshot of susceptibility trends for pathogens on Curaçao, an island in the southern Caribbean.MethodsWe analyzed susceptibility data of bacterial pathogens isolated from samples submitted from patients attending general practitioners, outpatient clinics and those who were hospitalized between January 2018 and December 2023. Samples originating from blood, urine, genital tract, soft tissue, and lungs were included. Susceptibility testing was performed by VITEK2 according using the European Committee on Antimicrobial Susceptibility Testing criteria.ResultsIn total, 13,528 patients contributed to 22,876 first isolates. Of all infections in adults with Staphylococcus aureus, 14% (95% confidence interval 10–18%) were methicillin-resistant S. aureus (MRSA) in blood, and up to 27% (20–35%) in soft-tissue cultures. For Escherichia coli and Klebsiella pneumoniae, resistance levels were up to 27% (95% CI 22–32%) for cefuroxime and up to 18% (95% CI 18–28%) for third-generation cephalosporins. The addition of gentamicin to empirical therapy with cefuroxime increased coverage only moderately, especially in K. pneumoniae (16%, 95% CI 12–20%). Resistance to amoxicillin-clavulanic acid was up to 47% (95% CI 43–50%), to ciprofloxacin 34% (95% CI 31–37%) and to cotrimoxazole 37% (95% CI 34–39) in urine cultures from outpatients. In contrast, low levels of carbapenem resistant Enterobacterales and Pseudomonas aeruginosa were observed.ConclusionsAntimicrobial resistance is high and widespread across several important antibiotic classes. The widespread occurrence of MRSA and resistance to third-generation cephalosporins highlights the importance of identifying risk factors, enabling more effective guidance for antimicrobial stewardship.

Unraveling genetic similarities of Klebsiella pneumoniae from poultry and poultry handlers in Punjab, India

The study aimed to characterize K. pneumoniae isolates from poultry (broiler) farms of Ludhiana, Punjab, India. The Whole genome sequencing (WGS) of K. pneumoniae isolates (K. pneumoniae strain PF_L1_IN, K. pneumoniae strain PF_L2_IN, K. pneumoniae strain PHS_IN) using NovaSeq6000 (Illumina, USA) platform revealed the presence of several antimicrobial resistant genes (ARGs) on the genome of the isolates conferring potential resistance to antibiotics classified as critically important, highly important and important. The virulence factors (VFs) detected were Type I fimbriae, Type 3 fimbriae, AcrAB, Aerobactin, Enterobactin, Salmochelin, RcsAB, T6SS-I, II and III. The mobile genetic elements such as plasmid replicons (IncFIB and Col440I), integron elements (In0, CALIN), a unit transposon (Tn512) and insertion sequences (ISKpn24, ISEc9, ISKpn1, IS102, IS903, IS5075 and ISKpn38) were detected in the isolates. The plasmids carried ARGs for the important antibiotic classes such as aminoglycoside, macrolides, quinolones, tetracyclines, carbapenems and sulphonamides. However, none of the insertion sequences and transposons in the isolates was associated with any antimicrobial resistant gene. In multilocus sequence typing (MLST) analysis, the isolates belonged to sequence type (ST) ST-147 and ST-147 with double locus variation, while, in core-genome multilocus sequence typing (cgMLST) the isolates belonged to ST-25590 and ST-1508. The isolates from broiler (K. pneumoniae strain PF_L1_IN) and its handler (K. pneumoniae strain PHS_IN) showed clonal relationship. The present study suggested that the food animal's production environment could act as a reservoir of multidrug resistant (MDR) and Extended spectrum β-lactamases (ESBL) producing K. pneumoniae. These resistant isolates could easily be disseminated to human through shared environment and food.

Time-resolved crystallography of boric acid binding to the active site serine of the β-lactamase CTX-M-14 and subsequent 1,2-diol esterification

The emergence and spread of antibiotic resistance represent a growing threat to public health. Of particular concern is the appearance of β-lactamases, which are capable to hydrolyze and inactivate the most important class of antibiotics, the β-lactams. Effective β-lactamase inhibitors and mechanistic insights into their action are central in overcoming this type of resistance, and in this context boronate-based β-lactamase inhibitors were just recently approved to treat multidrug-resistant bacteria. Using boric acid as a simplified inhibitor model, time-resolved serial crystallography was employed to obtain mechanistic insights into binding to the active site serine of β-lactamase CTX-M-14, identifying a reaction time frame of 80–100 ms. In a next step, the subsequent 1,2-diol boric ester formation with glycerol in the active site was monitored proceeding in a time frame of 100–150 ms. Furthermore, the displacement of the crucial anion in the active site of the β-lactamase was verified as an essential part of the binding mechanism of substrates and inhibitors. In total, 22 datasets of β-lactamase intermediate complexes with high spatial resolution of 1.40–2.04 Å and high temporal resolution range of 50–10,000 ms were obtained, allowing a detailed analysis of the studied processes. Mechanistic details captured here contribute to the understanding of molecular processes and their time frames in enzymatic reactions. Moreover, we could demonstrate that time-resolved crystallography can serve as an additional tool for identifying and investigating enzymatic reactions.

Multidrug Resistance And Susceptibility Profile of Outpatient Escherichia Coli Clinical Isolates

Background: To gain better understanding about the impact of antibiotic selection pressure on antimicrobial resistance (AMR) in Nigeria, it is important to conduct and review from time to time the susceptibility profile of clinically important bacteria including Escherichia coli. This study investigated the susceptibility and multidrug resistance profile of E. coli isolates from urine samples of patients who received outpatient’s medical services in Abakaliki. Methods: A total of 50 non-duplicate clinical isolates of E. coli from the microbiology laboratory section of a tertiary hospital in Abakaliki, Nigeria was recruited for this study. Susceptibility studies were determined using amoxicillin (20 µg), ceftazidime (30 µg), ciprofloxacin (5 µg), gentamicin (10 µg), nitrofurantoin (300 µg) and erythromycin acid (15 µg) by the modified Kirby–Bauer disk diffusion method. All susceptibility studies were carried out as per the guidelines of the Clinical Laboratory Standard Institute (CLSI). Multidrug resistance was evaluated by the multiple antibiotic resistance index (MARI) calculation. Results: The E. coli isolates showed reduced susceptibility to gentamicin (75%), ciprofloxacin (85%), nitrofurantoin (95%), amoxicillin (100%), erythromycin (100%) and ceftazidime (95%). A total of 12 E. coli isolates were multidrug resistant to clinically important antibiotics in the classes: cephalosporins, macrolides, aminoglycosides, fluoroquinolones, penicillins and nitrofurantoin. Conclusion: We report a high rate of antibiotic resistance of outpatients E. coli isolates which concurrently showed multidrug resistance to important antibiotic classes. These findings have clinical significance and provide a benchmark for future studies on the susceptibility pattern of clinical isolates in Nigeria. This preliminary study reiterates the need to reinvigorate antibiotic stewardship in our local hospitals so as to preserve the clinical efficacy of available antibiotics since it takes years for a new antibiotic to be developed.

Nα-Aroyl-N-Aryl-Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non-tuberculous mycobacteria (NTM) has also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, in vitro microbiological profiling, structure-activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.

Recent development and fighting strategies for lincosamide antibiotic resistance.

SUMMARYLincosamides constitute an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. However, due to the misuse of lincosamide and co-selection pressure, the resistance to lincosamide has become a serious concern. It is urgently needed to carefully understand the phenomenon and mechanism of lincosamide resistance to effectively prevent and control lincosamide resistance. To date, six mobile lincosamide resistance classes, including lnu, cfr, erm, vga, lsa, and sal, have been identified. These lincosamide resistance genes are frequently found on mobile genetic elements (MGEs), such as plasmids, transposons, integrative and conjugative elements, genomic islands, and prophages. Additionally, MGEs harbor the genes that confer resistance not only to antimicrobial agents of other classes but also to metals and biocides. The ultimate purpose of discovering and summarizing bacterial resistance is to prevent, control, and combat resistance effectively. This review highlights four promising strategies, including chemical modification of antibiotics, the development of antimicrobial peptides, the initiation of bacterial self-destruct program, and antimicrobial stewardship, to fight against resistance and safeguard global health.

Dihydrophenazine: a multifunctional new weapon that kills multidrug-resistant Acinetobacter baumannii and restores carbapenem and oxidative stress susceptibilities.

The current work aims to fully characterize a new antimicrobial agent against Acinetobacter baumannii, which continues to represent a growing threat to healthcare settings worldwide. With minimal treatment options due to the extensive spread of resistance to almost all the available antimicrobials, the hunt for new antimicrobial agents is a high priority. An Egyptian soil-derived bacterium strain NHM-077B proved to be a promising source for a new antimicrobial agent. Bio-guided fractionation of the culture supernatants of NHM-077B followed by chemical structure elucidation identified the active antimicrobial agent as 1-hydroxy phenazine. Chemical synthesis yielded more derivatives, including dihydrophenazine (DHP), which proved to be the most potent against A. baumannii, yet it exhibited a marginally safe cytotoxicity profile against human skin fibroblasts. Proteomics analysis of the cells treated with DHP revealed multiple proteins with altered expression that could be correlated to the observed phenotypes and potential mechanism of the antimicrobial action of DHP. DHP is a multipronged agent that affects membrane integrity, increases susceptibility to oxidative stress, interferes with amino acids/protein synthesis, and modulates virulence-related proteins. Interestingly, DHP in subinhibitory concentrations re-sensitizes the highly virulent carbapenem-resistant A. baumannii strain AB5075 to carbapenems providing great hope in regaining some of the benefits of this important class of antibiotics. This work underscores the potential of DHP as a promising new agent with multifunctional roles as both a classical and nonconventional antimicrobial agent that is urgently needed.

Pyrene-Based Nanoporous Covalent Organic Framework for Carboxylation of C-H Bonds with CO2 and Value-Added 2-Oxazolidinones Synthesis under Ambient Conditions.

The selective carbon capture and utilization (CCU) as a one-carbon (C1) feedstock offers dual advantages for mitigating the rising atmospheric CO2 content and producing fine chemicals/fuels. In this context, herein, we report the application of a porous bipyridine-functionalized, pyrene-based covalent organic framework (Pybpy-COF) for the stable anchoring of catalytic Ag(0) nanoparticles (NPs) and its catalytic investigation for fixation of CO2 to commodity chemicals at ambient conditions. Notably, Ag@Pybpy-COF showed excellent catalytic activity for the carboxylation of various terminal alkynes to corresponding alkynyl carboxylic acids/phenylpropiolic acids via C-H bond activation under atmospheric pressure conditions. Besides, carboxylative cyclization of various propargylic amines with CO2 to generate 2-oxazolidinones, an important class of antibiotics, has also been achieved under mild conditions. This significant catalytic activity of Ag@Pybpy-COF with wide functional group tolerance is rendered by the presence of highly exposed, alkynophilic Ag(0) catalytic sites decorated on the pore walls of high surface area (787 m2 g-1) Pybpy-COF. Further, density functional theory calculations unveiled the detailed mechanistic path of the Ag@Pybpy-COF-catalyzed transformation of CO2 to alkynyl carboxylic acids and 2-oxazolidinones. Moreover, the catalyst showed high recyclability for several cycles of reuse without significant loss in its catalytic activity and structural rigidity. This work demonstrates the promising application of Pybpy-COF for stable anchoring of Ag NPs for successful transformation of CO2 to valuable commodity chemicals at ambient conditions.

Human carriage of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae in relation to the consumption of raw or undercooked vegetables, fruits, and fresh herbs.

We investigated to what extent the consumption of raw or undercooked vegetables, fruits, and fresh herbs influences carriage rates of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in the general population. We assessed long-term carriage and changes in ESBL-E/K prevalence over time, by comparing the results to findings in the same population 5 years earlier. Between July and December 2021, participants sent in two fecal samples and questionnaires, 3 months apart. Food frequency questionnaires were sent on a monthly basis. Fecal samples were cultured and screened for ESBL-E/K, and phenotypically positive isolates were sequenced. Multivariable logistic regression models were established to assess the association between the consumption of fresh produce and ESBL-E/K carriage. The ESBL-E/K prevalence was 7.6% [41/537; 95% confidence interval (CI): 5.7-10.2] in the first sampling round and 7.0% (34/489; 95% CI: 5.0-9.6) in the second. Multivariable models did not result in statistical significance for any of the selected fruit and vegetable types. Trends for increased carriage rates were observed for the consumption of raspberry and blueberry in the summer period. ESBL-E/K prevalence was comparable with the prevalence in the same cohort 5 years earlier (7.5%; 95% CI: 5.6-10.1%). In six persons (1.2%) a genetically highly homologous ESBL-E/K was found. In conclusion, the contribution of the consumption of raw fruits, vegetables, and herbs to ESBL-E/K carriage in humans in the Netherlands is probably low. Despite COVID-19 containment measures (e.g., travel restrictions, social distancing, and hygiene) the ESBL-E/K prevalence was similar to 5 years earlier. Furthermore, indications for long-term carriage were found.IMPORTANCEESBL-producing bacteria are resistant against important classes of antibiotics, including penicillins and cephalosporines, which complicates treatment of infections. Food is one of the main routes of transmission for carriage of these bacteria in the general population. Although fruits, vegetables, and herbs are generally less frequently contaminated with ESBL-producing bacteria compared to meat, exposure might be higher since these products are often eaten raw or undercooked. This research showed that the contribution of the consumption of raw or undercooked fresh produce to ESBL-E/K carriage in the general Dutch population was low. No specific types of fruit or vegetables could be identified that gave a higher risk of carriage. In addition, we demonstrated the presence of genetically highly homologous ESBL-E/K in six persons after a period of 5 years, indicative for long-term carriage.

Metabolic and transcriptional activities underlie stationary-phase Pseudomonas aeruginosa sensitivity to Levofloxacin.

The bacterial pathogen Pseudomonas aeruginosa is responsible for a variety of chronic human infections. Even in the absence of identifiable resistance mutations, this pathogen can tolerate lethal antibiotic doses through phenotypic strategies like biofilm formation and metabolic quiescence. In this study, we determined that P. aeruginosa maintains greater metabolic activity in the stationary phase compared to the model organism, Escherichia coli, which has traditionally been used to study fluoroquinolone antibiotic tolerance. We demonstrate that hallmarks of E. coli fluoroquinolone tolerance are not conserved in P. aeruginosa, including the timing of cell death and necessity of the SOS DNA damage response for survival. The heightened sensitivity of stationary-phase P. aeruginosa to fluoroquinolones is attributed to maintained transcriptional and reductase activity. Our data suggest that perturbations that suppress transcription and respiration in P. aeruginosa may actually protect the pathogen against this important class of antibiotics.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

Antibiotic Resistance Genes Carried by Commensal Escherichia coli from Shelter Cats in Italy.

Antimicrobial resistance is a widespread global health problem. The presence of resistant bacteria and antibiotic resistance genes has been demonstrated not only in humans but also in animals, including pets. Stray cats share the urban environment with people and pets. This may facilitate transmission of resistant bacteria and resistance genes between stray animals, people and domestic animals. Several studies have investigated the role of stray cats as a fecal carrier of ESBL-producing bacteria. However, there are many genes and resistance mechanisms that can be detected in commensal E. coli, which, because of its genetic plasticity, is considered an indicator for monitoring antibiotic resistance. In this study, rectal swabs were collected from stray cats from colonies and shelters in the city of Monza (Monza Brianza, Italy) to isolate commensal E. coli. Phenotypic tests, such as the minimum inhibitory concentration (MIC) and the double disc test (DDST), and molecular analyses to detect antimicrobial resistance genes (ARGs) were used to study the resistance of these isolates. The results obtained confirm that stray cats can carry ESBL-producing E. coli (6.7%) and genes conferring resistance to other important antibiotic classes such as tetracyclines and sulfonamides.

Epidemiology of vancomycin-resistant enterococci in the United Arab Emirates: a retrospective analysis of 12 years of national AMR surveillance data.

Enterococci are usually low pathogenic, but can cause invasive disease under certain circumstances, including urinary tract infections, bacteremia, endocarditis, and meningitis, and are associated with peritonitis and intra-abdominal abscesses. Increasing resistance of enterococci to glycopeptides and fluoroquinolones, and high-level resistance to aminoglycosides is a concern. National antimicrobial resistance (AMR) surveillance data for enterococci from the Middle East and North Africa (MENA) and the Gulf region is scarce. A retrospective 12-year analysis of N = 37,909 non-duplicate diagnostic Enterococcus spp. isolates from the United Arab Emirates (UAE) was conducted. Data was generated by routine patient care during 2010-2021, collected by trained personnel and reported by participating surveillance sites to the UAE National AMR Surveillance program. Data analysis was conducted with WHONET. Enterococcus faecalis was the most commonly reported species (81.5%), followed by Enterococcus faecium (8.5%), and other enterococci species (4.8%). Phenotypically vancomycin-resistant enterococci (VRE) were found in 1.8% of Enterococcus spp. isolates. Prevalence of VRE (%VRE) was highest for E. faecium (8.1%), followed by E. faecalis (0.9%). A significant level of resistance to glycopeptides (%VRE) for these two species has been observed in the majority of observed years [E. faecalis (0-2.2%), 2010: 0%, 2021: 0.6%] and E. faecium (0-14.2%, 2010: 0%, 2021: 5.8%). Resistance to fluoroquinolones was between 17 and 29% (E. faecalis) and was higher for E. faecium (between 42 and 83%). VRE were associated with higher patient mortality (RR: 2.97), admission to intensive care units (RR: 2.25), and increased length of stay (six excess inpatient days per VRE case), as compared to vancomycin-susceptible Enterococcus spp. Published data on Enterococcus infections, in particular VRE-infections, in the UAE and MENA region is scarce. Our data demonstrates that VRE-enterococci are relatively rare in the UAE, however showing an increasing resistance trend for several clinically important antibiotic classes, causing a concern for the treatment of serious infections caused by enterococci. This study also demonstrates that VRE were associated with higher mortality, increased intensive care unit admission rates, and longer hospitalization, thus poorer clinical outcome and higher associated costs in the UAE. We recommend the expansion of current surveillance techniques (e.g., local VRE screening), stricter infection prevention and control strategies, and better stewardship interventions. Further studies on the molecular epidemiology of enterococci are needed.

Multiresidue method for the determination of critically and highly important classes of antibiotics and their metabolites in agricultural soils and sewage sludge

In this paper, a method is proposed for the determination of antibiotics classified by the World Health Organization as critically important (four macrolides and three quinolones) and highly important (one tetracycline, one diaminopyridine, and three sulfonamides) and eight of their metabolites. The method is based on ultrasound-assisted extraction, dispersive solid-phase extraction clean-up, and analytical determination by liquid chromatography–tandem mass spectrometry. Variables affecting each stage of the analytical method were thoroughly optimised. The method was validated for its application to sewage sludge from different treatment stages (non-treated sludge: primary and secondary sludge; and treated sludge: digested sludge and compost) and to agricultural soil. Limits of quantification were in the range of 0.03–7.50 ng g−1 dry weight (dw) for most of the compounds. Accuracy values were in the range of 70–102%. Precision was below 17%. The application of the method to real samples revealed that macrolides and fluoroquinolones were the antibiotic classes at the highest concentrations in all types of samples. The lowest concentrations of antibiotics were measured in compost (highest concentration: 27 ng g−1 dw, corresponding to norfloxacin) and soil samples (highest concentration: 93 ng g−1 dw, corresponding to a metabolite of clarithromycin). The proposed method is the first developed to date for the determination of multiclass antibiotics and their main metabolites in sludge from different treatment stages. The method can provide a useful tool for obtaining information about antibiotics in sewage sludge prior to its application to agricultural soils and in agricultural soils.Graphical

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis.

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.

Search for Novel Halophilic and Halotolerant Producers of Antimicrobial Compounds in Various Extreme Ecosystems

Abstract—The recent increase of antibiotic resistance in pathogenic microorganisms stimulated interest in the search for new antimicrobial compounds and their producers. Among the latter, halophilic microorganisms are considered to be the most promising group, since actinomycetes, producers of the majority of the known clinically important classes of antibiotics, are widely represented in this group. The present work reports the results of the search with three different approaches for new antimicrobial compounds in halophilic and halotolerant microorganisms inhabiting three different types of extreme ecosystems. Metagenomic analysis of microbial communities of subsurface thermal mineral waters revealed biosynthetic clusters of putative antimicrobial compounds, which belong to bacteria and archaea of uncultured lineages. Enrichment cultures with antimicrobial activity were obtained from the cold, deep oceanic sediments; analysis of their phylogenetic diversity resulted in identification of the potential producers of antimicrobial compounds as the members of class Desulfuromonadia. Finally, antimicrobial activity of a new species of soil natronophilic streptomycetes, Streptomyces sp. ACA25, was characterized; it was active only against gram-positive bacteria. The genome of this organism was sequenced, and the pathways for biosynthesis of polypeptide, polyketide, and beta-lactam antibiotics were identified. Active fractions of the ACA25 culture, containing antimicrobial compounds of polyketide and beta-lactam nature, were obtained. The active polyketide was identified as rosamycin, an antibiotic of the macrolide structural group. However, the fact that it did not inhibit bacterial translation highlighted structural differences between the new polyketide and rosamycin.

Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.

Tetracyclines (TCs) are an important class of antibiotics threatened by an emerging new resistance mechanism─enzymatic inactivation. These TC-inactivating enzymes, also known as tetracycline destructases (TDases), inactivate all known TC antibiotics, including drugs of last resort. Combination therapies consisting of a TDase inhibitor and a TC antibiotic represent an attractive strategy for overcoming this type of antibiotic resistance. Here, we report the structure-based design, synthesis, and evaluation of bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). By appending a nicotinamide isostere to the C9 position of the aTC D-ring, we generated bisubstrate TDase inhibitors. The bisubstrate inhibitors have extended interactions with TDases by spanning both the TC and presumed NADPH binding pockets. This simultaneously blocks TC binding and the reduction of FAD by NADPH while "locking" TDases in an unproductive FAD "out" conformation.

Repurposing β-Lactams for the Treatment of Mycobacterium kansasii Infections: An In Vitro Study.

Mycobacterium kansasii (Mkn) causes tuberculosis-like lung infection in both immunocompetent and immunocompromised patients. Current standard therapy against Mkn infection is lengthy and difficult to adhere to. Although β-lactams are the most important class of antibiotics, representing 65% of the global antibiotic market, they have been traditionally dismissed for the treatment of mycobacterial infections, as they were considered inactive against mycobacteria. A renewed interest in β-lactams as antimycobacterial agents has shown their activity against several mycobacterial species, including M. tuberculosis, M. ulcerans or M. abscessus; however, information against Mkn is lacking. In this study, we determined the in vitro activity of several β-lactams against Mkn. A selection of 32 agents including all β-lactam chemical classes (penicillins, cephalosporins, carbapenems and monobactams) with three β-lactamase inhibitors (clavulanate, tazobactam and avibactam) were evaluated against 22 Mkn strains by MIC assays. Penicillins plus clavulanate and first- and third-generation cephalosporins were the most active β-lactams against Mkn. Combinatorial time-kill assays revealed favorable interactions of amoxicillin-clavulanate and cefadroxil with first-line Mkn treatment. Amoxicillin-clavulanate and cefadroxil are oral medications that are readily available, and well tolerated with an excellent safety and pharmacokinetic profile that could constitute a promising alternative option for Mkn therapy.

Analysis of antibiotic resistance from a rural community and wastewater contaminated environment linked to human and animal activities

Antimicrobial resistance poses serious socioeconomic and ecological threat globally, warranting innovative approaches for surveillance and monitoring. One Health concept was considered in the analysis of soil, animal feces, pond water, wastewater and vegetable samples from a rural community and the environment in Palapye, Botswana. Culture-dependent and next-generation sequencing approaches were used for characterization of bacteria and antibiotic resistance genes. Viable potentially pathogenic bacteria exhibiting multi-drug resistance profiles corresponding to various clinically relevant antibiotics were observed. Next-generation sequence analysis also reveals occurrence and diversity of bacterial communities and acquired antibiotic resistance genes corresponding to clinically important classes of antibiotics (beta-lactam, aminoglycoside, tetracycline, fosfomycin, trimethoprim, sulfonamide, quinolone, macrolide, and phenicol). High diversity was observed for beta-lactamase encoding (bla) genes from pond water in a rural community. Phylum gammaproteobacteria was revealed as the most abundant from metagenomics sequences of both community and environment samples. Multi-drug and heavy metal resistance encoding Serratia mercensens DM6 was identified from whole genome sequence data. This study serves as proof-of-concept for the application of next-generation sequencing in low- and middle-income countries and supports the One Health surveillance of antimicrobial resistance. The data generated can contribute towards antimicrobial stewardship programs and implementation of National Action Plan on antimicrobial resistance.

Synthesis, mechanism of action, and structure-activity relationships of 1,3-oxazolidinones as anti-bacterial Agent: A review

Background: 1,3-oxazolidinones are an important class of antibiotics that are recognized with higher activities against Gram-positive bacteria. linezolid, tedizolid phosphate, and radezolid are important examples of this group. Aim: The aim of this review is to study the effect of 1,3-oxazolidinone derivatives as Gram-positive antibacterial agents. Results: There are many methods for preparing the oxazolidinone derivatives. Many patents Three new antibacterial oxazolidinones are linezolid, tedizolid phosphate, and radezolid. They differ in the side chain according to their structure-activity relationship. Conclusion: Study the structure-activity relationship (SAR) of oxazolidinone derivatives as new antibacterial agents.