Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from <i>Neisseria gonorrhoeae</i>

Ammerman, Lauren; Mertz, Sarah B.; Park, Chanyang; Wise, John G.

doi:10.1021/acs.biochem.1c00399

Cited by 2 publications

(2 citation statements)

References 55 publications

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“…In the same year, Ammerman et al [ 105 ] studied substrate (azithromycin) and non-substrate (streptomycin) interactions and dynamics with the same RND transporter using free and targeted MD simulations. The authors determined the spontaneous diffusion of azithromycin through CH2 and found that it takes an unexpected pathway along PN1, bypassing the DP altogether.…”

Section: Mechanism Of Substrate Transportmentioning

confidence: 99%

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

et al. 2023

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Bacterial resistance to antibiotics has been long recognized as a priority to address for human health. Among all micro-organisms, the so-called multi-drug resistant (MDR) bacteria, which are resistant to most, if not all drugs in our current arsenal, are particularly worrisome. The World Health Organization has prioritized the ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Enterobacter species) pathogens, which include four Gram-negative bacterial species. In these bacteria, active extrusion of antimicrobial compounds out of the cell by means of ‘molecular guns’ known as efflux pumps is a main determinant of MDR phenotypes. The resistance-nodulation-cell division (RND) superfamily of efflux pumps connecting the inner and outer membrane in Gram-negative bacteria is crucial to the onset of MDR and virulence, as well as biofilm formation. Thus, understanding the molecular basis of the interaction of antibiotics and inhibitors with these pumps is key to the design of more effective therapeutics. With the aim to contribute to this challenge, and complement and inspire experimental research, in silico studies on RND efflux pumps have flourished in recent decades. Here, we review a selection of such investigations addressing the main determinants behind the polyspecificity of these pumps, the mechanisms of substrate recognition, transport and inhibition, as well as the relevance of their assembly for proper functioning, and the role of protein–lipid interactions. The journey will end with a perspective on the role of computer simulations in addressing the challenges posed by these beautifully complex machineries and in supporting the fight against the spread of MDR bacteria.

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Section: Mechanism Of Substrate Transportmentioning

confidence: 99%

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

et al. 2023

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“…These peptides likely enter gonococci and bind to this efflux pump and, as a consequence, decrease efflux activity. Advances in determining the structure of MtrD complexed with antibiotics in the proximal or deep binding pockets could facilitate structure-based approaches to develop specific, safe inhibitors that act at designated sites within this transporter [72–75]. With specific regard to gene regulation, the results of Chen et al .…”

Section: Exploiting Knowledge Of Regulation For Therapeutic Purposesmentioning

confidence: 99%

Transcriptional regulation of the mtrCDE efflux pump operon: importance for Neisseria gonorrhoeae antimicrobial resistance

2022

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This review focuses on the mechanisms of transcriptional control of an important multidrug efflux pump system (MtrCDE) possessed by Neisseria gonorrhoeae , the aetiological agent of the sexually transmitted infection termed gonorrhoea. The mtrCDE operon that encodes this tripartite protein efflux pump is subject to both cis- and trans-acting transcriptional factors that negatively or positively influence expression. Critically, levels of MtrCDE can influence levels of gonococcal susceptibility to classical antibiotics, host-derived antimicrobials and various biocides. The regulatory systems that control mtrCDE can have profound influences on the capacity of gonococci to resist current and past antibiotic therapy regimens as well as virulence. The emergence, mechanisms of action and clinical significance of the transcriptional regulatory systems that impact mtrCDE expression in gonococci are reviewed here with the aim of linking bacterial antimicrobial resistance with multidrug efflux capability.

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Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from Neisseria gonorrhoeae

Cited by 2 publications

References 55 publications

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

Transcriptional regulation of the mtrCDE efflux pump operon: importance for Neisseria gonorrhoeae antimicrobial resistance

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