Abstract

ABSTRACTGram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens.

Highlights

  • Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species

  • The gene encoding the recombinant EcPore was integrated onto the chromosomes of P. aeruginosa PAO1, A. baumannii ATCC 17978, B. thailandensis E264 (Bt), and B. cepacia ATCC 25416

  • The names of the strains comprise the strain abbreviation (Pa for P. aeruginosa PAO1, Abau [or Ab] for A. baumannii ATCC 17978, Bt for B. thailandensis, and Bc for B. cepacia ATCC 25416) followed by a designation representing the inducible promoter used for the induction (ARA for arabinose, LAC for IPTG [isopropyl-␤-D-thiogalactopyranoside], and rhamnose-inducible promoter (RHA) for rhamnose) and the name of the pore, if present

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Summary

Introduction

Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. The intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gramnegative bacteria from antibiotics. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery. Antibiotic-resistant Gram-negative bacterial species that have emerged in clinics have caused life-threatening infections that are effectively untreatable by antibiotic monotherapy [1, 2]. In all Gram-negative species, the low-permeability barrier of the outer membranes and multidrug efflux play key roles in resisting antibiotic challenges. Antibacterial activities of large and polar antibiotics exceeding the size of general porins (Ͼ600 Da in E. coli) are usually the most restricted by OM, whereas the zwitterionic character in compounds correlates with increased permeation across the OM [3, 8,9,10]

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