A “Drug Sweeping” State of the TriABC Triclosan Efflux Pump from Pseudomonas aeruginosa

Fabre, Lucien; Ntreh, Abigail T.; Yazidi, Amira; Leus, Inga V.; Weeks, Jon W.; Bhattacharyya, Sudipta; Ruickoldt, Jakob; Rouiller, Isabelle; Zgurskaya, Helen I.; Sygusch, J.

doi:10.1016/j.str.2020.09.001

Cited by 12 publications

(21 citation statements)

References 75 publications

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“…In the section below we try to integrate the latest structural advances in understanding of the RND assembly and the roles of the PAPs within it into an integrated model of assembly of the complex, which takes into account both the PAP−OMF and PAP−RND interactions. Corroborating the recent results on the MexAB-OprM 270,306 and TriABC-OpmH systems, 302 with the earlier allosteric model derived from the AcrAB-TolC discussed above, 305 we would like to suggest a modest modification of this model, incorporating a simple mechanism based on varying the affinities of the interprotomer binding sites created by the peristaltic cycling of the RND transporter toward the PAP2.…”

Section: Conformational Cycling Of the Protomers Within The Acrb/mexb...mentioning

confidence: 75%

“…Corroborating the recent results on the MexAB-OprM 270 , 306 and TriABC-OpmH systems, 302 with the earlier allosteric model derived from the AcrAB-TolC discussed above, 305 we would like to suggest a modest modification of this model, incorporating a simple mechanism based on varying the affinities of the interprotomer binding sites created by the peristaltic cycling of the RND transporter toward the PAP2.…”

Section: Assembly and Function Of The Rnd-based Tripartite Complexesmentioning

confidence: 75%

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Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria

et al. 2021

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Tripartite efflux pumps and the related type 1 secretion systems (T1SSs) in Gram-negative organisms are diverse in function, energization, and structural organization. They form continuous conduits spanning both the inner and the outer membrane and are composed of three principal components—the energized inner membrane transporters (belonging to ABC, RND, and MFS families), the outer membrane factor channel-like proteins, and linking the two, the periplasmic adaptor proteins (PAPs), also known as the membrane fusion proteins (MFPs). In this review we summarize the recent advances in understanding of structural biology, function, and regulation of these systems, highlighting the previously undescribed role of PAPs in providing a common architectural scaffold across diverse families of transporters. Despite being built from a limited number of basic structural domains, these complexes present a staggering variety of architectures. While key insights have been derived from the RND transporter systems, a closer inspection of the operation and structural organization of different tripartite systems reveals unexpected analogies between them, including those formed around MFS- and ATP-driven transporters, suggesting that they operate around basic common principles. Based on that we are proposing a new integrated model of PAP-mediated communication within the conformational cycling of tripartite systems, which could be expanded to other types of assemblies.

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Section: Conformational Cycling Of the Protomers Within The Acrb/mexb...mentioning

confidence: 75%

Section: Assembly and Function Of The Rnd-based Tripartite Complexesmentioning

confidence: 75%

Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria

et al. 2021

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“…343,344 A functional rotation through these three major conformations drives efflux of hundreds of structurally unrelated compounds by AcrB/MexB pumps 345 but also enables export of specific substrates such as heavy metals by CusA from E. coli or triclosan by TriABC from P. aeruginosa. 346,347 4.3.1. Substrate Binding and Affinities.…”

Section: Kinetic Properties Of Secondary Transportersmentioning

confidence: 99%

The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux

et al. 2021

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Cell envelope plays a dual role in the life of bacteria by simultaneously protecting it from a hostile environment and facilitating access to beneficial molecules. At the heart of this ability lie the restrictive properties of the cellular membrane augmented by efflux transporters, which preclude intracellular penetration of most molecules except with the help of specialized uptake mediators. Recently, kinetic properties of the cell envelope came into focus driven on one hand by the urgent need in new antibiotics and, on the other hand, by experimental and theoretical advances in studies of transmembrane transport. A notable result from these studies is the development of a kinetic formalism that integrates the Michaelis–Menten behavior of individual transporters with transmembrane diffusion and offers a quantitative basis for the analysis of intracellular penetration of bioactive compounds. This review surveys key experimental and computational approaches to the investigation of transport by individual translocators and in whole cells, summarizes key findings from these studies and outlines implications for antibiotic discovery. Special emphasis is placed on Gram-negative bacteria, whose envelope contains two separate membranes. This feature sets these organisms apart from Gram-positive bacteria and eukaryotic cells by providing them with full benefits of the synergy between slow transmembrane diffusion and active efflux.

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“…In this section, we provide an overview of conservation distilled from the comparison of numerous RND multidrug efflux pumps. We previously analyzed about 400 RND genes from Gram-negative gammaproteobacteria [15] (including heavy metal efflux pumps (HME) [59,60], heteromultimeric MdtBC-like pumps [59,61,62] and others such as TriClike efflux pumps [63,64]). For this review, we specifically selected from that database 133 homotrimeric multidrug efflux pump genes and added the sequences of MtrD-Ng and AdeG-Ab, converted the DNA sequences to amino acid sequences and performed protein multiple sequence alignment [65] on a total of 135 pumps.…”

Section: Conservation Among Rnd Efflux Pumps Highlights Important Domainsmentioning

confidence: 99%

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Zwama

Nishino

2021

Antibiotics

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The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.

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A “Drug Sweeping” State of the TriABC Triclosan Efflux Pump from Pseudomonas aeruginosa

Cited by 12 publications

References 75 publications

Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria

Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria

The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

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