Understanding the Molecular Pathways of Colistin Heteroresistance in Multidrug-Resistant Acinetobacter baumannii

Background: A.baumannii is a critical nosocomial pathogen with increasing antibiotic resistance. Heterogeneous resistance to colistin (CHR), which cannot be detected by standard methods, threatens the effectiveness of this definitive treatment. This study aimed to characterize carbapenem resistance, detect CHR, and investigate its molecular mechanisms. Methods: Two hundred A.baumannii isolates were characterized. Carbapenemase genes were detected by PCR, and antibiotic susceptibility was determined by disc diffusion and broth microdilution. Heterogeneous resistance was detected using population analysis profiling (PAP). The expression of efflux pump (adeB, adeG) and purine (ompA, carO) genes in HR isolates quantified by Real-time PCR analysis Results: The predominant carbapenemase genes were blaOXA-51 (97%), blaOXA-23 (88%), and blaOXA-24-40 (72%). PAP revealed a prevalence of 8.5% (3/35) of CHR among carbapenem-resistant and colistin-susceptible isolates. Real-time PCR revealed a highly significant (p<0.001) increase in expression of adeB and adeG (approximately 4-fold) and a concomitant decrease in expression of ompA and carO in these isolates, suggesting a synergistic adaptation mechanism. Conclusion: This study highlights the need for proactive monitoring of CHR for clinical surveillance and management to prevent the emergence of full-scale resistance. Therapeutically, the development of efflux pump inhibitors and molecular diagnostics could be crucial to maintain colistin efficacy and improve treatment outcomes.