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Antimicrobial resistance (AMR) is the ability of microbes to survive exposure to antimicrobials that were once effective against them. This is a major global crisis and public health challenge of the 21st century that is declared as a silent pandemic, with India among other countries considered one of the hotspots [R. Laxminarayan, A. Duse, C. Wattal, A. K. M. Zaidi, et al., Lancet Infect Dis 13:1057-1098, 2013, https://doi.org/10.1016/S1473-3099(13)70318-9]. The evolution of AMR in modern India's context is embedded in a complex interplay of the timing of antibiotic introduction, a growing dense population, cultural inheritances, infectious disease burden, developing health systems, evolving drug market regulations, environmental and animal sector drivers, socioeconomic factors, and policy/implementation gaps. Central to this discussion are the human patient, animal, and environmental aspects of antibiotic overuse from the historical aspects of AMR in India broadly tracing from early antibiotic use to the current \"One Health\" challenge. It highlights cultural factors, the evolution of surveillance systems, policy responses, India's efforts, and key lessons in antimicrobial stewardship.

The alarming rise of Acinetobacter baumannii producing New Delhi Metallo-β-lactamase (NDM) threatens last-line antibiotic therapies. While β-lactamase dissemination is often accounted for the underlying genetics, the biochemical mechanisms involved in the adaptation of these enzymes within specific bacterial hosts are scarcely known. Here, we show that the stability of NDM differs significantly between A. baumannii and Escherichia coli , due to the varying roles of periplasmic proteases involved in NDM degradation in each host. Variant NDM-5 exhibits enhanced stability and confers increased antibiotic resistance in A. baumannii under zinc-limited conditions (common in infection sites). These findings underscore the role of host-specific proteostasis in shaping the adaptation of resistance determinants and suggest new strategies to combat antibiotic resistance.

Infections caused by carbapenem-resistant Enterobacterales (CRE) pose significant threats to patients and public health worldwide. Carbapenem resistance can occur through several molecular mechanisms, including enzymatic hydrolysis by carbapenemases and reduced influx via porin mutations. Identifying carbapenemase-producing isolates could enable tailored antibiotic selection to improve patient outcomes and infection control measures to prevent further carbapenemase transmission. In a large collection of CRE isolates, we found that only carbapenemase-producing CRE exhibited an inoculum effect, in which their measured resistance varies markedly with cell density, which risks misdiagnosis. Further, this inoculum effect occurred under conditions where bacteria released carbapenemases to the community upon exposure to antibiotics that resulted in cell death. Measuring this inoculum effect, or integrating other data from routine antimicrobial susceptibility testing, enhanced carbapenem resistance detection, paving the way for more effective strategies to combat this growing public health crisis.

Antimicrobial resistance (AMR) is one of the most urgent health threats of the 21st century. Surveillance is needed to enable timely interventions, close knowledge gaps, and anticipate long-term trends. Current frameworks rely heavily on clinical data, which often fail to capture population-level dynamics. Wastewater-based surveillance (WBS) offers a complementary approach by detecting antibiotic resistance genes (ARGs) in sewage. In AMR surveillance, early warning includes the detection of novel or clinically relevant ARGs, including those carried by mobile genetic elements (MGEs) before they affect clinical outcomes. WBS can also reveal resistome composition, dissemination routes, and ecological drivers of AMR. This is especially relevant in settings with poor sanitation, high exposure, and limited clinical reporting. Unlocking its potential will require harmonized protocols, sustained investment, and strong ethical measures. Within a One Health framework, WBS can strengthen equitable and evidence-based strategies against AMR.

Methicillin-resistant Staphylococcus aureus remains a leading cause of antibiotic-resistant infections worldwide, and its lineages can differ widely in antibiotic resistance and virulence. In this study, we compared the North American USA300 lineage (ST8) with an emerging East Asian ST72 strain, SAWL001. SAWL001 showed higher resistance to several antibiotics than USA300, although the overall resistance levels were moderate. Also, SAWL001 exhibits an inducible mecA- mediated methicillin resistance, whereas USA300 expresses mecA constitutively. Conversely, USA300 invades host epithelial cells more effectively and survives oxidative stress better than SAWL001. Genome and transcriptome analyses show that USA300 retains classical virulence factors, while SAWL001 is primed for horizontal gene acquisition. Our findings underscore distinct evolutionary strategies: USA300 appears to favor aggressive virulence, whereas SAWL001 shows greater metabolic and genomic flexibility, suggesting the need for lineage-specific control strategies.

The global emergence of Staphylococcus aureus ST188 poses new challenges to public health due to its ability to infect both humans and animals and spread across regions and continents. Despite its growing prevalence, little has been known about its evolutionary history and dissemination patterns. In this study, we analyzed 808 ST188 genomes from 24 countries and found evidence of frequent cross-regional and cross-host transmission. Two major clades, showing clear clonal expansion, were dominated by isolates from China. We also identified a newly emerged methicillin-resistant subclade likely derived from a methicillin-susceptible ancestor, characterized by the acquisition of SCC mec IVa, multiple resistance genes, and fluoroquinolone-resistance mutations. This subclade exhibited reduced adhesion and colonization capacity due to structural loss of key virulence genes. These findings provide new insights into the clade-specific adaptation and global spread of ST188 and underscore the need for genomic surveillance of multidrug-resistant S. aureus emerging from traditionally susceptible lineages.

Antimicrobial resistance (AMR), a global threat, challenges early diagnosis and treatment of tuberculosis (TB). This study employs TIES_PM, a free-energy calculation method, to efficiently predict AMR by quantifying how mutations in bacterial RNA polymerase (RNAP) affect rifampicin (RIF) binding. On simulating 61 clinically observed mutations, the results align with WHO classifications and reveal ambiguous cases, suggesting alternative resistance mechanisms. Each mutation requires ~5 h, offering rapid, cost-effective predictions. An ensemble approach ensures statistical robustness. TIES_PM can be extended to smaller proteins for systematic codon permutation analysis, enabling comprehensive antibiotic resistance prediction, or adapted to identify low-resistance-risk drug leads. It also applies to other TB drugs and resistant pathogens, supporting personalized therapy and global AMR surveillance. This work provides novel tools to refine resistance mutation databases and phenotypic classification standards, enhancing early diagnosis while advancing translational research and infectious disease control.

Staphylococcus aureus causes both hospital- and community-acquired infections worldwide. Methicillin-resistant S. aureus is best known and has spread across the globe. Whole-genome sequencing (WGS) can type strains at the highest resolution. To enable best use of WGS data for surveillance of S. aureus , this study developed a multilevel genome typing (MGT) scheme that provides a publicly available, standardized, flexible, and easily communicated system to describe S. aureus strains. MGT has eight typing levels that provide progressively higher resolution. Each of these levels allows subtypes to be accurately identified and tracked. We show that MGT can be used to track well-known S. aureus strains at low resolution while simultaneously being able to track outbreaks in hospital settings at high resolution. The S. aureus MGT will facilitate the use of genomic data for surveillance without the need for bioinformatic expertise, improving efforts to control this important pathogen and prevent infections.

Ceftriaxone remains the last reliable option for gonorrhea therapy, yet recurrent infections can occur despite isolates being classified as susceptible by MIC testing. One possible explanation is antibiotic tolerance, a phenotype that allows survival during drug exposure without changes in MIC. Although tolerance has been described in other pathogens, its role in gonococcal infection has remained poorly defined. In this study, we provide the first detailed characterization of a ceftriaxone-tolerant Neisseria gonorrhoeae clinical isolate associated with repeated treatment failure. By combining in vitro killing assays, an in vivo Galleria mellonella infection model, whole-genome sequencing, and transcriptomic profiling, we demonstrate that tolerance enables prolonged survival under ceftriaxone and is linked to pilin gene variation and ribosomal remodeling. These findings illustrate how a clinically observed phenomenon can be mechanistically dissected and emphasize tolerance as a hidden factor contributing to gonococcal persistence and potential treatment failure.

This study provides a detailed analysis of carbapenem-resistant Klebsiella pneumoniae (CRKP) transmission dynamics in neonatal intensive care units (NICUs) over eight years, utilizing 64 isolates and applying machine learning to identify risk factors associated with persistence and spread. Through phylogenetic analyses, we uncovered three clonal outbreaks and linked healthcare group (HG) interactions, bacterial genotypes, and plasmid prevalence to short- and long-term CRKP transmission. We identified that HGs are primary mediators of rapid, short-term transmission, while specific plasmids play an extended role in maintaining CRKP presence across multiple patient cohorts and bacterial strains. This finding suggests the existence of latent reservoirs or periodic reintroductions from external sources, thus reshaping the understanding of NICU-associated pathogen transmission and persistence.