Resusceptibility to Ceftazidime-Avibactam in Tigecycline-Exposed NDM-Producing CRECC

Purpose Carbapenem-resistant Enterobacter cloacae complex (CRECC) has become an increasingly important pathogen in healthcare-associated infections, with limited treatment options and a high mortality rate. As reports of antimicrobial resistance continue to rise, tigecycline (TGC) and ceftazidime-avibactam (CZA) have emerged as the last-line therapies for CRECC infections. The aim of this study was to investigate collateral sensitivity to ceftazidime-avibactam following the acquisition of tigecycline resistance in NDM-producing CRECC, and to elucidate the underlying molecular mechanisms, thereby providing a theoretical basis for clinical combination therapy. Methods Antimicrobial susceptibility profiles were determined using the broth microdilution method, and changes in colony morphology were analyzed. Transcriptomic sequencing was performed to characterize global gene expression alterations associated with antimicrobial resistance, and an in vivo Galleria mellonella infection model was used to assess the virulence of the mutant strains. Results Both drug-resistant mutants displayed a stable mucoid phenotype with marked collateral susceptibility to CZA, with minimum inhibitory concentrations decreasing from greater than 128 mg/L to 0.5–1 mg/L. Compared with the parental strains, these mutants showed thickened cell surface structures, impaired growth, reduced serum tolerance, and significantly attenuated virulence in the Galleria mellonella infection model. Transcriptomic analysis indicated increased extracellular polysaccharide production, impaired lipid A modification associated with reduced phoQ expression, and markedly decreased expression of metallo- β -lactamase-related genes, including NDM and CTX-M. Conclusion We hypothesize that the susceptibility of metallo- β -lactamase-producing strains to CZA represents an adaptive survival modification, which is achieved by reducing metallo- β -lactamase expression and altering bacterial metabolism at the cost of impaired bacterial growth and pathogenicity. This trade-off between antimicrobial resistance and bacterial fitness offers novel insights into the development of optimized therapeutic strategies for CRECC infections.