Integrated Phenotypic, Molecular, and Genomic Analysis of Antimicrobial Resistance in Yersinia pestis Isolates from Natural Plague Foci of Kazakhstan

Plague remains a globally significant zoonotic infection maintained in natural foci, with ongoing epizootic activity and periodic human cases reported in different regions of the world. Continuous monitoring of antimicrobial susceptibility of Yersinia pestis is essential due to the potential emergence and spread of resistant strains. A total of 75 Yersinia pestis isolates, including clinical and epizootic strains obtained from plague outbreaks in Kazakhstan, were analyzed. Antimicrobial susceptibility was evaluated using standard phenotypic methods, and molecular screening for resistance determinants was performed by real-time PCR. Genome-level analysis based on whole-genome sequencing (WGS) data from the NCBI BioProject PRJNA1249055 was conducted to assess the presence of acquired antimicrobial resistance genes and chromosomal mutations associated with resistance. All isolates demonstrated high susceptibility to clinically relevant antibiotics. No resistance genes were detected by molecular screening. Genome-based analysis confirmed the absence of acquired antimicrobial resistance determinants, resistance-associated mutations in key loci (rpsL, gyrA, parC), and plasmid-mediated resistance mechanisms. Minor lineage-associated variation in phoP was identified in a limited number of isolates and was not associated with antimicrobial resistance. These findings indicate a stable antimicrobial susceptibility profile of Yersinia pestis in Kazakhstan and confirm the absence of emerging resistance despite long-term circulation in natural plague foci. The results highlight the importance of integrated surveillance and support the continued effectiveness of current therapeutic strategies for plague.