Physiological Functions of Bacterial “Multidrug” Efflux Pumps

Abstract

Bacterial multidrug efflux pumps have come to prominence in human and veterinary pathogenesis because they help bacteria protect themselves against the antimicrobials used to overcome their infections. However, it is increasingly realized that many, probably most, such pumps have physiological roles that are distinct from protection of bacteria against antimicrobials administered by humans. Here we undertake a broad survey of the proteins involved, allied to detailed examples of their evolution, energetics, structures, chemical recognition, and molecular mechanisms, together with the experimental strategies that enable rapid and economical progress in understanding their true physiological roles. Once these roles are established, the knowledge can be harnessed to design more effective drugs, improve existing microbial production of drugs for clinical practice and of feedstocks for commercial exploitation, and even develop more sustainable biological processes that avoid, for example, utilization of petroleum.

Towards robust Pseudomonas cell factories to harbour novel biosynthetic pathways

“…The active extrusion of molecules plays a major role in the resistance of bacteria towards various toxic compounds because the invasion of toxic chemicals cannot be prevented completely by cell envelope stress response mechanisms (Figure 1C). Implicated efflux transporters are structurally and mechanistically diverse [50] and are categorised into different families [51] (Table 1).…”

Host - Bacterial Pathogen Communication: The Wily Role of the Multidrug Efflux Pumps of the MFS Family

“…Efflux pumps are ubiquitous transmembrane transporters able to extrude a variety of toxic compounds, including drugs from the cell ( Nikaido and Pagès, 2012 ; Du et al, 2018 ; Henderson et al, 2021 ). The association of efflux pumps (EPs) with drug resistance was first suggested about 4 decades ago ( Ball et al, 1980 ; McMurry et al, 1980 ).…”

“…Tripartite EPs are constituted by an inner membrane transporter protein connected with an outer membrane factor (OMF) via a periplasmic adaptor protein (PAP) ( Hinchliffe et al, 2013 ; Alav et al, 2021 ). MDR EPs have been identified within all major families of transporters, i.e., the Resistance Nodulation Division (RND), the ATP Binding Cassette (ABC), the Major Facilitator Superfamily (MFS), the Multidrug and Toxic Compound Extrusion (MATE), the Drug/Metabolite transporter (DMT), the Proteobacterial Antimicrobial Compound Efflux (PACE) family and the p-aminobenzoyl-glutamate Transporter (abgT) ( Henderson et al, 2021 ). The main energy source utilized by MDR EPs is the proton motive force.…”

“…The main energy source utilized by MDR EPs is the proton motive force. Members of the ABC family rely on ATP hydrolysis ( Du et al, 2018 ; Henderson et al, 2021 ) ( Figure 1 ).…”

“…In this context it is worth mentioning that MDR EPs contribute to inter-bacterial communication, to biofilm formation, and to the interactions with plant and animal cells ( Alcalde-Rico et al, 2016 ; Alav et al, 2018 ; Pasqua et al, 2019b ). As most genes encoding MDR EPs are highly conserved and reside within the bacterial core genome, the ability of MDR EPs to facilitate antibiotic resistance is currently regarded as a fortuitous by-product of an ancient physiological function ( Saier et al, 1998 ; Neyfakh, 2002 ; Teelucksingh et al, 2020 ; Henderson et al, 2021 ). This is further stressed by the fact that, based on their antibiotic extruding activity, most MDR EPs are functionally redundant and operate on the same substrate ( Tal and Schuldiner, 2009 ; Nikaido and Pagès, 2012 ; Henderson et al, 2021 ).…”