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The advent of multidrug resistance among pathogenic bacteria is imperiling the worth of antibiotics, which have previously transformed medical sciences. The crisis of antimicrobial resistance has been ascribed to the misuse of these agents and due to unavailability of newer drugs attributable to exigent regulatory requirements and reduced financial inducements. Comprehensive efforts are needed to minimize the pace of resistance by studying emergent microorganisms, resistance mechanisms, and antimicrobial agents. Multidisciplinary approaches are required across health care settings as well as environment and agriculture sectors. Progressive alternate approaches including probiotics, antibodies, and vaccines have shown promising results in trials that suggest the role of these alternatives as preventive or adjunct therapies in future.

New Delhi Metallo- -lactamase producing (NDM-1-KP) sequence type (ST) 147 poses a significant threat in clinical settings due to its evolution into two distinct directions: hypervirulence and carbapenem resistance. Hypervirulence results from a range of virulence factors, while carbapenem resistance stems from complex biological mechanisms. The NDM-1-KP ST147 clone has emerged as a recent addition to the family of successful clones within the species. In this study, we successfully synthesized 5-bromo- -alkylthiophene-2-sulfonamides ( ) by reacting 5-bromothiophene-2-sulfonamide ( ) with various alkyl bromides ( ) using LiH. We also synthesized a series of compounds ( ) from compound ( ) using the Suzuki-Miyaura cross-coupling reaction with fair to good yields (56-72%). Further, we screened the synthesized molecules against clinically isolated New Delhi Metallo- -lactamase producing ST147. Subsequently, we conducted in-silico tests on compound against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I. The compound ( ) with favourable drug candidate status, MIC of 0.39 μg/mL, and MBC of 0.78 μg/mL. This low molecular weight compound exhibited the highest potency against the resistant bacterial strains. The in-silico tests revealed that the compound against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I demonstrated H-bond and hydrophobic interactions. The 5-bromo- -alkylthiophene-2-sulfonamides displayed antibacterial efficacy against New Delhi Metallo- -lactamase producing ST147. After the in-vivo trial, this substance might offer an alternative therapeutic option.

Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host’s immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects.

Colonization of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae as animal gut microbiota is a substantial global threat. This study aimed to determine the molecular characterization of bla SHV , bla TEM , and bla CTX-M variants in animals, as well as to evaluate the antimicrobial resistance conferred by these genes. We prospectively analyzed 1273 fecal specimens of farm and domestic animals for the isolation of enterobacteria that had the ESBL phenotype by using biochemical methods. The extracted genes were amplified by polymerase chain reaction and sequenced for the characterization of bla SHV , bla TEM , and bla CTX-M variants. The drug-resistance spectrum and hierarchical clusters were analyzed against 19 antibacterial agents. Out of 245 (19.2%) ESBL enterobacteria, 180 (75.5%) Escherichia coli and 34 (13.9%) Klebsiella pneumoniae were prevalent species. A total of 73.9% bla CTX-M , 26.1% bla TEM , and 14.2% bla SHV were found among the enterobacteria; however, their association with farm or domestic animals was not statistically significant. The distribution of bla gene variants showed the highest number of bla CTX-M-1 (133; 54.3%), followed by bla CTX-M-15 (28; 11.4%), bla TEM-52 (40; 16.3%), and bla SHV-12 (22; 9%). In addition, 84.5% of the enterobacteria had the integrons intI1 . We observed ±100% enterobacteria resistant to cephalosporin, 7 (2.9%) to colistin (minimum inhibitory concentration breakpoint ≥4 μg/mL), 9 (3.7%) to piperacillin-tazobactam, 11 (4.5%) to imipenem, 14 (5.7%) to meropenem, and 18 (7.3%) to cefoperazone-sulbactam, without statistically significant association. Animal gut microbiota contain a considerable number of bla CTX-M , bla TEM , bla SHV , and integrons, which are a potential source of acquired extensive drug resistance in human strains and leaves fewer therapeutic substitutes.

A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A–4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The results indicated that the majority of compounds showed promising effective in vitro antibacterial activity. Herein, 2-ethylhexyl-5-(p-tolyl)thiophene-2-carboxylate (4F), in particular among the synthesized analogs, showed outstanding antibacterial action (MIC value 3.125 mg/mL) against XDR Salmonella Typhi compared to ciprofloxacin and ceftriaxone. The intermolecular interaction was investigated by using a molecular docking study of thiophene derivatives 4A–4G against XDR S. Typhi. The values of the binding affinity of functionalized thiophene molecules and ciprofloxacin were compared against bacterial enzyme PDB ID: 5ztj. Therefore, 4F appears to be a promising antibacterial agent and showed the highest potential value. Density functional theory (DFT) calculations were executed to examine the electronic, structural, and spectroscopic features of the newly synthesized molecules 4A–4G.

Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi ( S . Typhi), the cause of typhoid fever, is one primary cause of pediatric sepsis in typhoid endemic areas. Extensively drug-resistant (XDR) S . Typhi is more common among pediatric patients, which is responsible for over 90% of the reported XDR typhoid cases, but the majority of antibiotic resistance studies available have been carried out using S . Typhi isolates from adult patients. Here, we characterized antibiotic-resistance profiles of XDR S . Typhi isolates from a medium size cohort of pediatric typhoid patients (n = 45, 68.89% male and 31.11% female) and determined antibiotic-resistance-related gene signatures associated with common treatment options to typhoid fever patients of 18 XDR S . Typhi representing all 45 isolates. Their ages were 1–13 years old: toddlers aging 1–2 years old (n = 9, 20%), pre-schoolers aging 3–5 years old (n = 17, 37.78%), school-age children aging 6–12 years old (n = 17, 37.78%), and adolescents aging 13–18 years old (n = 2, 4.44%). Through analyzing bla TEM1 , dhfR7 , sul1 , and catA1 genes for multidrug-resistance, qnrS , gyrA , gyrB , parC , and parE for fluoroquinolone-resistance, bla CTX-M-15 for XDR, and macAB and acrAB efflux pump system-associated genes, we showed the phenotype of the XDR S . Typhi isolates matches with their genotypes featured by the acquisitions of the genes bla TEM1 , dhfR7 , sul1 , catA1 , qnrS , and bla CTX-M-15 and a point mutation on gyrA . This study informs the molecular basis of antibiotic-resistance among recent S . Typhi isolates from pediatric septicemia patients, therefore providing insights into the development of molecular detection methods and treatment strategies for XDR S . Typhi.

Antibiotic-resistant bacteria causing foodborne serious illnesses can be found in contaminated food. Therefore, this study aimed to identify the pathogens, genes, and antimicrobial residues present in raw milk and meat. We collected 40 raw milk and 40 beef samples using the aseptic method from various parts of the Faisalabad metropolis, Pakistan. The samples were cultured on blood, MacConkey, and UTI chrome agar. The VITEK 2 compact system was used for microbial identification and determination of minimum inhibitory concentrations. Antimicrobial resistance genes for extended-spectrum β-lactamases, methicillin resistance in Staphylococcus aureus, and carbapenem resistance were identified using molecular techniques. ELISA was used to determine the tetracycline residue level in each sample. The beef samples showed polymicrobial contamination with 64 bacterial isolates, with Escherichia coli (29; 45.3%) and Klebsiella pneumoniae (11; 17.1%) predominating. The milk samples showed polymicrobial contamination with 73 bacterial isolates, with E. coli (22; 30%), K. pneumoniae (12; 16.4%), and S. aureus (10; 13.6%) forming the majority. Twenty-eight (43.7%) isolates from beef harbored tet genes, nineteen (29.6%) blaCTX-M, and fourteen (21.8%) blaNDM-1, and twenty-six (35.6%) isolates from milk harbored tet genes, nineteen (26%) blaTEM and blaCTX-M, and three (4%) blaNDM-1. Twenty-two (55%) each of the beef and milk samples exceeded the maximum residue limit for tetracycline. Polymicrobial contamination by bacteria possessing blaCTX-M, blaTEM, blaNDM-1, blaOXA, mecA, and tet genes was identified in food samples. The high tetracycline residue levels pose a serious health risk to consumers.

Antimicrobial resistance (AMR) has become a global burden, with inappropriate antibiotic prescribing being an important contributing factor. Antibiotic prescribing guidelines play an important role in improving the quality of antibiotic use, provided they are evidence-based and regularly updated. As a result, they help reduce AMR, which is a critical challenge in low- and middle-income countries (LMICs). Consequently, the objective of this study was to evaluate local, national, and international antibiotic prescribing guidelines currently available-especially among LMICs-and previous challenges, in light of the recent publication of the WHO AWaRe book, which provides future direction. Google Scholar and PubMed searches were complemented by searching official country websites to identify antibiotic prescribing guidelines, especially those concerning empiric treatment of bacterial infections, for this narrative review. Data were collected on the country of origin, income level, guideline title, year of publication, development methodology, issuing organization, target population, scope, and coverage. In addition, documentation on implementation strategies, compliance, monitoring of outcome measures, and any associated patient education or counseling efforts were reviewed to assess guideline utilization. A total of 181 guidelines were included, with the majority originating from high-income countries (109, 60.2%), followed by lower-middle-income (40, 22.1%), low-income (18, 9.9%), and upper-middle-income (14, 7.7%) countries. The GRADE methodology was used in only 20.4% of the sourced guidelines, predominantly in high-income countries. Patient education was often underemphasized, particularly in LMICs. The findings highlighted significant disparities in the development, adaptation, and implementation of guidelines across different WHO regions, confirming the previously noted lack of standardization and comprehensiveness in LMICs. Significant disparities exist in the availability, structure, and methodological rigor of antibiotic prescribing guidelines across countries with different income levels. Advancing the development and implementation of standardized, context-specific guidelines aligned with the WHO AWaRe framework-and supported by equity-focused reforms-can significantly strengthen antimicrobial stewardship and help address the public health challenge of AMR.

Development in the fields of natural-product-derived and synthetic small molecules is in stark contrast to the ongoing demand for novel antimicrobials to treat life-threatening infections caused by extended-spectrum β-lactamase producing Escherichia coli (ESBL E. coli). Therefore, there is an interest in the antibacterial activities of synthesized N-(4-methylpyridin-2-yl) thiophene-2-carboxamides (4a–h) against ESBL-producing E. coli ST131 strains. A blood sample was obtained from a suspected septicemia patient and processed in the Bactec Alert system. The isolate’s identification and antibacterial profile were determined using the VITEK 2® compact system. Multi-locus sequence typing of E. coli was conducted by identifying housekeeping genes, while ESBL phenotype detection was performed according to CLSI guidelines. Additionally, PCR was carried out to detect the blaCTX-M gene molecularly. Moreover, molecular docking studies of synthesized compounds (4a–h) demonstrated the binding pocket residues involved in the active site of the β-lactamase receptor of E. coli. The result confirmed the detection of E. coli ST131 from septicemia patients. The isolates were identified as ESBL producers carrying the blaCTX-M gene, which provided resistance against cephalosporins and beta-lactam inhibitors but sensitivity to carbapenems. Among the compounds tested, 4a and 4c exhibited high activity and demonstrated the best fit and interactions with the binding pocket of the β-lactamase enzyme. Interestingly, the maximum of the docking confirmations binds at a similar pocket region, further strengthening the importance of binding residues. Hence, the in vitro and molecular docking studies reflect the promising antibacterial effects of 4a and 4c compounds.

The emergence of extensively drug-resistant Salmonella Typhi (XDR-S. Typhi) poses a grave public health threat due to its resistance to fluoroquinolones and third-generation cephalosporins. This resistance significantly complicates treatment options, underscoring the urgent need for new therapeutic strategies. In this study, we synthesized pyrazine carboxamides (3, 5a–5d) in good yields through the Suzuki reaction. Afterward, we evaluate their antibacterial activities against XDR-S. Typhi via the agar well diffusion method; 5d has the strongest antibacterial activity with MIC 6.25 (mg/mL). Moreover, in vitro Alkaline Phosphatase inhibitor activity was also determined; 5d is the most potent compound, with an IC50 of 1.469 ± 0.02 µM. Further, in silico studies were performed to find the type of interactions between synthesized compounds and target proteins.