Efflux pumps in gram-negative bacteria play a critical role in antibiotic resistance by actively exporting a wide range of drugs from the cell. In Acinetobacter baumannii , one of the major hospital pathogens worldwide, the AdeABC efflux pump has been strongly associated with multidrug resistance, particularly in Türkiye where carbapenem resistance exceeds 90%. AdeC, the system’s outer membrane channel, provides the final exit for substrates, yet the structural and functional consequences of its sequence variation remain undefined. Here, we combine sequence analysis and molecular simulations to explore the efflux mechanism of AdeC. AdeC homologs were collected and aligned to identify a Turkish clinical variant carrying multiple amino acid substitutions distributed across the protein. Structural models of both the reference and variant AdeC were generated and subsequently embedded into the outer membrane of A . baumannii . To investigate efflux of antibiotics, antibiotic-bound systems were subjected to steered molecular dynamics, where we compared how different drug classes—β-lactams, carbapenems, and the β-lactamase inhibitors interact with the two AdeC variants during efflux. We identified variant-specific differences in channel flexibility and locations of shifted drug interactions which elucidate altered resistance phenotypes. We construct a computational framework for investigating AdeC-mediated efflux at atomic resolution, providing a basis for understanding how sequence variation shapes efflux mechanism and capacity.
Mazmanoglu et al. (Sun,) studied this question.