Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

Abstract

The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism.

What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

“…However, significant progress has been made in understanding aspects of the individual components of the overall process of drug expulsion. For example, a recent systematic study of the interaction of eight carbapenem antibiotics with the distal pocket (DP) of AcrB predicted how the physicochemical characteristics of the antibiotics may impact their binding preference [108]. In particular, Atzori et al found a correlation between the molecular weight of the carbapenems and the specific location of sub-pockets within the DP to which they preferentially bind.…”

Insights into Carbapenem Resistance in Vibrio Species: Current Status and Future Perspectives

“…According to the sequence similarity, the efflux system can be broadly classified into five distinct families [ 42 , 47 , 168 ]. More extensive characterization work has been conducted for other species, such as P. aeruginosa [ 170 , 171 ] and E. coli [ 172 , 173 ]. Still, information is relatively sparse for Vibrio spp.…”

MexAB-OprM Efflux Pump Interaction with the Peptidoglycan of Escherichia coli and Pseudomonas aeruginosa

“…The structure of each protein forming the pump has been solved by X-ray crystallography [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and the whole assembly was recently determined by cryo-electron microscopy (cryo-EM) [ 13 , 14 , 15 , 16 ]. The comparison of these structures from several homologous pumps, together with in vitro measurements of transport through proteoliposomes [ 17 , 18 ], in cellulo determination of the minimal inhibitory concentration (MIC) of antibiotics for mutant strains [ 19 , 20 ], and the extensive modeling and molecular dynamic calculations [ 21 , 22 ], have led to a more precise understanding of the efflux pathways [ 23 , 24 , 25 , 26 , 27 , 28 ] and the conformational modifications [ 14 , 29 , 30 ] necessary to expulse the drugs out of the cell. We know now that the RND protein works as homotrimer with a proton motive force via proton relay amino acids localized in the membranous domain.…”