Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance

ABSTRACT 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 resistan...

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Autores principales:	Meinan Lyu, Mitchell A. Moseng, Jennifer L. Reimche, Concerta L. Holley, Vijaya Dhulipala, Chih-Chia Su, William M. Shafer, Edward W. Yu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	cryo-EM Neisseria gonorrhoeae efflux pumps multidrug resistance structural biology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/38956fe7f1b843b0a44c5ce5d08045e4
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spelling	oai:doaj.org-article:38956fe7f1b843b0a44c5ce5d08045e42021-11-15T15:56:47ZCryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance10.1128/mBio.00996-202150-7511https://doaj.org/article/38956fe7f1b843b0a44c5ce5d08045e42020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00996-20https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Neisseria 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.Meinan LyuMitchell A. MosengJennifer L. ReimcheConcerta L. HolleyVijaya DhulipalaChih-Chia SuWilliam M. ShaferEdward W. YuAmerican Society for Microbiologyarticlecryo-EMNeisseria gonorrhoeaeefflux pumpsmultidrug resistancestructural biologyMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cryo-EM Neisseria gonorrhoeae efflux pumps multidrug resistance structural biology Microbiology QR1-502
spellingShingle	cryo-EM Neisseria gonorrhoeae efflux pumps multidrug resistance structural biology Microbiology QR1-502 Meinan Lyu Mitchell A. Moseng Jennifer L. Reimche Concerta L. Holley Vijaya Dhulipala Chih-Chia Su William M. Shafer Edward W. Yu Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
description	ABSTRACT 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. IMPORTANCE Neisseria 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.
format	article
author	Meinan Lyu Mitchell A. Moseng Jennifer L. Reimche Concerta L. Holley Vijaya Dhulipala Chih-Chia Su William M. Shafer Edward W. Yu
author_facet	Meinan Lyu Mitchell A. Moseng Jennifer L. Reimche Concerta L. Holley Vijaya Dhulipala Chih-Chia Su William M. Shafer Edward W. Yu
author_sort	Meinan Lyu
title	Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
title_short	Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
title_full	Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
title_fullStr	Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
title_full_unstemmed	Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance
title_sort	cryo-em structures of a gonococcal multidrug efflux pump illuminate a mechanism of drug recognition and resistance
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/38956fe7f1b843b0a44c5ce5d08045e4
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Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance

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