Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa

Abstract

The permeability barrier of Gram-negative cell envelopes is the major obstacle in the discovery and development of new antibiotics. In Gram-negative bacteria, these difficulties are exacerbated by the synergistic interaction between two biochemically distinct phenomena, the low permeability of the outer membrane (OM) and active multidrug efflux. In this study, we used Pseudomonas aeruginosa and Escherichia coli strains with controllable permeability barriers, achieved through hyperporination of the OMs and varied efflux capacities, to evaluate the contributions of each of the barriers to protection from antibacterials. We analyzed antibacterial activities of β-lactams and fluoroquinolones, antibiotics that are optimized for targets in the periplasm and the cytoplasm, respectively, and performed a machine learning-based analysis to identify physicochemical descriptors that best classify their relative potencies. Our results show that the molecular properties selected by active efflux and the OM barriers are different for the two species. Antibiotic activity in P. aeruginosa was better classified by electrostatic and surface area properties, whereas topology, physical properties, and atom or bond counts best capture the behavior in E. coli. In several cases, descriptor values that correspond to active antibiotics also correspond to significant barrier effects, highlighting the synergy between the two barriers where optimizing for one barrier promotes strengthening of the other barrier. Thus, both barriers should be considered when optimizing antibiotics for favorable OM permeability, efflux evasion, or both.

Alternating Dynamics of oriC , SMC, and MksBEF in Segregation of Pseudomonas aeruginosa Chromosome

“…To further substantiate this prediction, we quantified the occurrence of anucleate cells in strains deficient for condensins and ParB. To facilitate uniform DNA staining, we used efflux-deficient PΔ6Pore cells, which are susceptible to numerous drugs (33). In agreement with previous studies (19), the deletion of mksB and smc resulted in a modest increase in anucleate cell formation (Fig.…”

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…Moreover, in several cases descriptor values corresponding to active antibiotics and significant barrier effects overlapped, which highlights the synergy between the two barriers. Further, it suggests that molecular properties of antibiotics should be optimized in parallel to achieve favorable outer membrane permeability and to evade efflux …”

“…Further, it suggests that molecular properties of antibiotics should be optimized in parallel to achieve favorable outer membrane permeability and to evade efflux. 267 It seems paradoxical that a single, low molecular weight and drug-like compound could exist that would counter the activity of drug efflux, when the MDR efflux pumps are well crafted to handle such structurally diverse compounds. 128 Resolved crystal structures and homology models enable a deeper insight into the structure and function of the major efflux pumps present in WHO priority pathogens, which will hopefully yield a clinically useful EPI.…”

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

“…Despite the recognized role of RND efflux systems in multi-drug resistance to antibiotics, a quantitative assessment of their contribution remains challenging due to the difficulties in the determination of the efflux kinetics of most substrates of AcrB and homologous RND transporters [58,63,64]. While for other drugs the binding to AcrB has been characterized structurally [32,34,36] and/or by means of site-directed mutagenesis [65][66][67] to the best of our knowledge for the carbapenems investigated in this study, the available data possibly related to efflux-mediated resistance are the variations in the MIC values of antibiotics upon deletion of the outer membrane transporter TolC and/or AcrB (or homologous proteins see e.g., [68][69][70]). These data, however, notoriously reflect additional processes involving antibiotics and other bacterial components [53].…”