Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection

ABSTRACT Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates (“hypermutation”) may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play a...

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Autores principales:	Pavel P. Khil, Augusto Dulanto Chiang, Jonathan Ho, Jung-Ho Youn, Jamie K. Lemon, Juan Gea-Banacloche, Karen M. Frank, Mark Parta, Robert A. Bonomo, John P. Dekker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Pseudomonas aeruginosa antimicrobial agents bacterial evolution ceftazidime-avibactam host-pathogen interactions hypermutator Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7f73195dff6c40008b4e1528001c23e0
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spelling	oai:doaj.org-article:7f73195dff6c40008b4e1528001c23e02021-11-15T15:59:41ZDynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection10.1128/mBio.01822-192150-7511https://doaj.org/article/7f73195dff6c40008b4e1528001c23e02019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01822-19https://doaj.org/toc/2150-7511ABSTRACT Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates (“hypermutation”) may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demonstrate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a patient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was differentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hypermutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolution experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance compared with the isogenic wild-type strain. Our results suggest a possibly underappreciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection. IMPORTANCE Antimicrobial resistance in bacteria represents one of the most consequential problems in modern medicine, and its emergence and spread threaten to compromise central advances in the treatment of infectious diseases. Ceftazidime-avibactam (CZA) belongs to a new class of broad-spectrum beta-lactam/beta-lactamase inhibitor combinations designed to treat infections caused by multidrug-resistant bacteria. Understanding the emergence of resistance to this important new drug class is of critical importance. In this work, we demonstrate that evolved mismatch repair deficiency in P. aeruginosa, an important pathogen responsible for significant morbidity and mortality among hospitalized patients, may facilitate rapid acquisition of resistance to CZA in the context of acute infection. These findings are relevant for both diagnosis and treatment of antimicrobial resistance emerging in acute infection in the hypermutator background and additionally have implications for the emergence of more virulent phenotypes.Pavel P. KhilAugusto Dulanto ChiangJonathan HoJung-Ho YounJamie K. LemonJuan Gea-BanaclocheKaren M. FrankMark PartaRobert A. BonomoJohn P. DekkerAmerican Society for MicrobiologyarticlePseudomonas aeruginosaantimicrobial agentsbacterial evolutionceftazidime-avibactamhost-pathogen interactionshypermutatorMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pseudomonas aeruginosa antimicrobial agents bacterial evolution ceftazidime-avibactam host-pathogen interactions hypermutator Microbiology QR1-502
spellingShingle	Pseudomonas aeruginosa antimicrobial agents bacterial evolution ceftazidime-avibactam host-pathogen interactions hypermutator Microbiology QR1-502 Pavel P. Khil Augusto Dulanto Chiang Jonathan Ho Jung-Ho Youn Jamie K. Lemon Juan Gea-Banacloche Karen M. Frank Mark Parta Robert A. Bonomo John P. Dekker Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
description	ABSTRACT Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates (“hypermutation”) may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demonstrate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a patient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was differentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hypermutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolution experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance compared with the isogenic wild-type strain. Our results suggest a possibly underappreciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection. IMPORTANCE Antimicrobial resistance in bacteria represents one of the most consequential problems in modern medicine, and its emergence and spread threaten to compromise central advances in the treatment of infectious diseases. Ceftazidime-avibactam (CZA) belongs to a new class of broad-spectrum beta-lactam/beta-lactamase inhibitor combinations designed to treat infections caused by multidrug-resistant bacteria. Understanding the emergence of resistance to this important new drug class is of critical importance. In this work, we demonstrate that evolved mismatch repair deficiency in P. aeruginosa, an important pathogen responsible for significant morbidity and mortality among hospitalized patients, may facilitate rapid acquisition of resistance to CZA in the context of acute infection. These findings are relevant for both diagnosis and treatment of antimicrobial resistance emerging in acute infection in the hypermutator background and additionally have implications for the emergence of more virulent phenotypes.
format	article
author	Pavel P. Khil Augusto Dulanto Chiang Jonathan Ho Jung-Ho Youn Jamie K. Lemon Juan Gea-Banacloche Karen M. Frank Mark Parta Robert A. Bonomo John P. Dekker
author_facet	Pavel P. Khil Augusto Dulanto Chiang Jonathan Ho Jung-Ho Youn Jamie K. Lemon Juan Gea-Banacloche Karen M. Frank Mark Parta Robert A. Bonomo John P. Dekker
author_sort	Pavel P. Khil
title	Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
title_short	Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
title_full	Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
title_fullStr	Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
title_full_unstemmed	Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection
title_sort	dynamic emergence of mismatch repair deficiency facilitates rapid evolution of ceftazidime-avibactam resistance in <named-content content-type="genus-species">pseudomonas aeruginosa</named-content> acute infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/7f73195dff6c40008b4e1528001c23e0
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Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Acute Infection

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