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Mg²⁺-dependent mechanism of environmental versatility in a multidrug efflux pump.

ABSTRACT: Tripartite resistance nodulation and cell division multidrug efflux pumps span the periplasm and are a major driver of multidrug resistance among Gram-negative bacteria. The periplasm provides a distinct environment between the inner and outer membranes of Gram-negative bacteria. Cations, such as Mg²⁺, become concentrated within the periplasm and, in contrast to the cytoplasm, its pH is sensitive to conditions outside the cell. Here, we reveal an interplay between Mg²⁺ and pH in modulating the dynamics of the periplasmic adaptor protein, AcrA, and its function within the prototypical AcrAB-TolC multidrug efflux pump from Escherichia coli. In the absence of Mg²⁺, AcrA becomes increasingly plastic within acidic conditions, but when Mg²⁺ is bound this is ameliorated, resulting in domain specific organisation in neutral to weakly acidic regimes. We establish a unique histidine residue directs these structural dynamics and is essential for sustaining pump efflux activity across acidic, neutral, and alkaline conditions. Overall, we propose Mg²⁺ conserves the structural mobility of AcrA to ensure optimal AcrAB-TolC function within rapid changing environments commonly faced by the periplasm during bacterial infection and colonization. This work highlights that Mg²⁺ is an important mechanistic component in this pump class and possibly across other periplasmic lipoproteins.

SUBMITTER: Lewis BR

PROVIDER: S-EPMC11195059 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Mg2+-dependent mechanism of environmental versatility in a multidrug efflux pump.

Lewis Benjamin Russell BR Uddin Muhammad R MR Kuo Katie M KM Shah Laila M N LMN Harris Nicola J NJ Booth Paula J PJ Hammerschmid Dietmar D Gumbart James C JC Zgurskaya Helen I HI Reading Eamonn E

bioRxiv : the preprint server for biology 20240610

Tripartite resistance nodulation and cell division multidrug efflux pumps span the periplasm and are a major driver of multidrug resistance among Gram-negative bacteria. The periplasm provides a distinct environment between the inner and outer membranes of Gram-negative bacteria. Cations, such as Mg2+, become concentrated within the periplasm and, in contrast to the cytoplasm, its pH is sensitive to conditions outside the cell. Here, we reveal an interplay between Mg2+ and ...[more]

PMID: 38915626

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Project description:Neisseria gonorrhoeae is an obligate human pathogen and causative agent of the sexually transmitted infection (STI) gonorrhea. The most predominant and clinically important multidrug efflux system in N. gonorrhoeae is the multiple transferrable resistance (Mtr) pump, which mediates resistance to a number of different classes of structurally diverse antimicrobial agents, including clinically used antibiotics (e.g., β-lactams and macrolides), dyes, detergents and host-derived antimicrobials (e.g., cationic antimicrobial peptides and bile salts). Recently, it has been found that gonococci bearing mosaic-like sequences within the mtrD gene can result in amino acid changes that increase the MtrD multidrug efflux pump activity, probably by influencing antimicrobial recognition and/or extrusion to elevate the level of antibiotic resistance. Here, we report drug-bound solution structures of the MtrD multidrug efflux pump carrying a mosaic-like sequence using single-particle cryo-electron microscopy, with the antibiotics bound deeply inside the periplasmic domain of the pump. Through this structural approach coupled with genetic studies, we identify critical amino acids that are important for drug resistance and propose a mechanism for proton translocation.IMPORTANCENeisseria gonorrhoeae has become a highly antimicrobial-resistant Gram-negative pathogen. Multidrug efflux is a major mechanism that N. gonorrhoeae uses to counteract the action of multiple classes of antibiotics. It appears that gonococci bearing mosaic-like sequences within the gene mtrD, encoding the most predominant and clinically important transporter of any gonococcal multidrug efflux pump, significantly elevate drug resistance and enhance transport function. Here, we report cryo-electron microscopy (EM) structures of N. gonorrhoeae MtrD carrying a mosaic-like sequence that allow us to understand the mechanism of drug recognition. Our work will ultimately inform structure-guided drug design for inhibiting these critical multidrug efflux pumps.

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Mg²⁺-dependent mechanism of environmental versatility in a multidrug efflux pump.

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Mg<sup>2+</sup>-dependent mechanism of environmental versatility in a multidrug efflux pump.

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Mg2+-dependent mechanism of environmental versatility in a multidrug efflux pump.

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Mg&lt;sup&gt;2+&lt;/sup&gt;-dependent mechanism of environmental versatility in a multidrug efflux pump.

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Mg²⁺-dependent mechanism of environmental versatility in a multidrug efflux pump.

Mg<sup>2+</sup>-dependent mechanism of environmental versatility in a multidrug efflux pump.