Identification of binding residues between periplasmic adapter protein (PAP) and RND efflux pumps explains PAP-pump promiscuity and roles in antimicrobial resistance

Autoři: Helen E. McNeil aff001;  Ilyas Alav aff001;  Ricardo Corona Torres aff002;  Amanda E. Rossiter aff001;  Eve Laycock aff001;  Simon Legood aff001;  Inderpreet Kaur aff001;  Matthew Davies aff001;  Matthew Wand aff003;  Mark A. Webber aff004;  Vassiliy N. Bavro aff002;  Jessica M. A. Blair aff001
Působiště autorů: Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom aff001;  School of Life Sciences, University of Essex, Colchester, United Kingdom aff002;  Public Health England, National Infection Service, Porton Down, Salisbury, Wiltshire, United Kingdom aff003;  Quadram Institute Bioscience, Norwich Research Park, Norwich, United Kingdom aff004
Vyšlo v časopise: Identification of binding residues between periplasmic adapter protein (PAP) and RND efflux pumps explains PAP-pump promiscuity and roles in antimicrobial resistance. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008101
Kategorie: Research Article


Active efflux due to tripartite RND efflux pumps is an important mechanism of clinically relevant antibiotic resistance in Gram-negative bacteria. These pumps are also essential for Gram-negative pathogens to cause infection and form biofilms. They consist of an inner membrane RND transporter; a periplasmic adaptor protein (PAP), and an outer membrane channel. The role of PAPs in assembly, and the identities of specific residues involved in PAP-RND binding, remain poorly understood. Using recent high-resolution structures, four 3D sites involved in PAP-RND binding within each PAP protomer were defined that correspond to nine discrete linear binding sequences or “binding boxes” within the PAP sequence. In the important human pathogen Salmonella enterica, these binding boxes are conserved within phylogenetically-related PAPs, such as AcrA and AcrE, while differing considerably between divergent PAPs such as MdsA and MdtA, despite overall conservation of the PAP structure. By analysing these binding sequences we created a predictive model of PAP-RND interaction, which suggested the determinants that may allow promiscuity between certain PAPs, but discrimination of others. We corroborated these predictions using direct phenotypic data, confirming that only AcrA and AcrE, but not MdtA or MsdA, can function with the major RND pump AcrB. Furthermore, we provide functional validation of the involvement of the binding boxes by disruptive site-directed mutagenesis. These results directly link sequence conservation within identified PAP binding sites with functional data providing mechanistic explanation for assembly of clinically relevant RND-pumps and explain how Salmonella and other pathogens maintain a degree of redundancy in efflux mediated resistance. Overall, our study provides a novel understanding of the molecular determinants driving the RND-PAP recognition by bridging the available structural information with experimental functional validation thus providing the scientific community with a predictive model of pump-contacts that could be exploited in the future for the development of targeted therapeutics and efflux pump inhibitors.

Klíčová slova:

Binding analysis – Bromides – Methylene blue – Multiple alignment calculation – Phenotypes – Salmonella – Sequence alignment – Sequence analysis


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