Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>

ABSTRACT Penicillin binding proteins (PBPs) are involved in peptidoglycan synthesis, and their inactivation is linked to β-lactamase expression in ampR–β-lactamase module–harboring Gram-negative bacteria. There are seven annotated PBP genes, namely, mrcA, mrcB, pbpC, mrdA, ftsI, dacB, and dacC, in t...

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Autores principales:	Yi-Wei Huang, Yu Wang, Yun Lin, Chin Lin, Yi-Tsung Lin, Cheng-Chih Hsu, Tsuey-Ching Yang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	beta-lactamases penicillin binding proteins peptidoglycan Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7ac2f3836eeb4544a167b104d831a375
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spelling	oai:doaj.org-article:7ac2f3836eeb4544a167b104d831a3752021-12-02T18:39:33ZImpacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>10.1128/mSystems.00077-172379-5077https://doaj.org/article/7ac2f3836eeb4544a167b104d831a3752017-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00077-17https://doaj.org/toc/2379-5077ABSTRACT Penicillin binding proteins (PBPs) are involved in peptidoglycan synthesis, and their inactivation is linked to β-lactamase expression in ampR–β-lactamase module–harboring Gram-negative bacteria. There are seven annotated PBP genes, namely, mrcA, mrcB, pbpC, mrdA, ftsI, dacB, and dacC, in the Stenotrophomonas maltophilia genome, and these genes encode PBP1a, PBP1b, PBP1c, PBP2, PBP3, PBP4, and PBP6, respectively. In addition, S. maltophilia harbors two β-lactamase genes, L1 and L2, whose expression is induced via β-lactam challenge. The impact of PBP inactivation on L1/L2 expression was assessed in this study. Inactivation of mrdA resulted in increased L1/L2 expression in the absence of β-lactam challenge, and the underlying mechanism was further elucidated. The roles of ampNG, ampDI (the homologue of Escherichia coli ampD), nagZ, ampR, and creBC in L1/L2 expression mediated by a ΔmrdA mutant strain were assessed via mutant construction and β-lactamase activity determinations. Furthermore, the strain ΔmrdA-mediated change in the muropeptide profile was assessed using liquid chromatography mass spectrometry (LC-MS). The mutant ΔmrdA-mediated L1/L2 expression relied on functional AmpNG, AmpR, and NagZ, was restricted by AmpDI, and was less related to the CreBC two-component system. Inactivation of mrdA significantly increased the levels of total and periplasmic N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamyl-meso-diamnopimelic acid-d-alanine (GlcNAc-anhMurNAc tetrapeptide, or M4N), supporting that the critical activator ligands for mutant strain ΔmrdA-mediated L1/L2 expression are anhMurNAc tetrapeptides. IMPORTANCE Inducible expression of chromosomally encoded β-lactamase(s) is a key mechanism for β-lactam resistance in Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The muropeptides produced during the peptidoglycan recycling pathway act as activator ligands for β-lactamase(s) induction. The muropeptides 1,6-anhydromuramyl pentapeptide and 1,6-anhydromuramyl tripeptide are the known activator ligands for ampC β-lactamase expression in E. cloacae. Here, we dissected the type of muropepetides for L1/L2 β-lactamase expression in an mrdA deletion mutant of S. maltophilia. Distinct from the findings with the ampC system, 1,6-anhydromuramyl tetrapeptide is the candidate for ΔmrdA-mediated β-lactamase expression in S. maltophilia. Our work extends the understanding of β-lactamase induction and provides valuable information for combating the occurrence of β-lactam resistance.Yi-Wei HuangYu WangYun LinChin LinYi-Tsung LinCheng-Chih HsuTsuey-Ching YangAmerican Society for Microbiologyarticlebeta-lactamasespenicillin binding proteinspeptidoglycanMicrobiologyQR1-502ENmSystems, Vol 2, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	beta-lactamases penicillin binding proteins peptidoglycan Microbiology QR1-502
spellingShingle	beta-lactamases penicillin binding proteins peptidoglycan Microbiology QR1-502 Yi-Wei Huang Yu Wang Yun Lin Chin Lin Yi-Tsung Lin Cheng-Chih Hsu Tsuey-Ching Yang Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
description	ABSTRACT Penicillin binding proteins (PBPs) are involved in peptidoglycan synthesis, and their inactivation is linked to β-lactamase expression in ampR–β-lactamase module–harboring Gram-negative bacteria. There are seven annotated PBP genes, namely, mrcA, mrcB, pbpC, mrdA, ftsI, dacB, and dacC, in the Stenotrophomonas maltophilia genome, and these genes encode PBP1a, PBP1b, PBP1c, PBP2, PBP3, PBP4, and PBP6, respectively. In addition, S. maltophilia harbors two β-lactamase genes, L1 and L2, whose expression is induced via β-lactam challenge. The impact of PBP inactivation on L1/L2 expression was assessed in this study. Inactivation of mrdA resulted in increased L1/L2 expression in the absence of β-lactam challenge, and the underlying mechanism was further elucidated. The roles of ampNG, ampDI (the homologue of Escherichia coli ampD), nagZ, ampR, and creBC in L1/L2 expression mediated by a ΔmrdA mutant strain were assessed via mutant construction and β-lactamase activity determinations. Furthermore, the strain ΔmrdA-mediated change in the muropeptide profile was assessed using liquid chromatography mass spectrometry (LC-MS). The mutant ΔmrdA-mediated L1/L2 expression relied on functional AmpNG, AmpR, and NagZ, was restricted by AmpDI, and was less related to the CreBC two-component system. Inactivation of mrdA significantly increased the levels of total and periplasmic N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamyl-meso-diamnopimelic acid-d-alanine (GlcNAc-anhMurNAc tetrapeptide, or M4N), supporting that the critical activator ligands for mutant strain ΔmrdA-mediated L1/L2 expression are anhMurNAc tetrapeptides. IMPORTANCE Inducible expression of chromosomally encoded β-lactamase(s) is a key mechanism for β-lactam resistance in Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The muropeptides produced during the peptidoglycan recycling pathway act as activator ligands for β-lactamase(s) induction. The muropeptides 1,6-anhydromuramyl pentapeptide and 1,6-anhydromuramyl tripeptide are the known activator ligands for ampC β-lactamase expression in E. cloacae. Here, we dissected the type of muropepetides for L1/L2 β-lactamase expression in an mrdA deletion mutant of S. maltophilia. Distinct from the findings with the ampC system, 1,6-anhydromuramyl tetrapeptide is the candidate for ΔmrdA-mediated β-lactamase expression in S. maltophilia. Our work extends the understanding of β-lactamase induction and provides valuable information for combating the occurrence of β-lactam resistance.
format	article
author	Yi-Wei Huang Yu Wang Yun Lin Chin Lin Yi-Tsung Lin Cheng-Chih Hsu Tsuey-Ching Yang
author_facet	Yi-Wei Huang Yu Wang Yun Lin Chin Lin Yi-Tsung Lin Cheng-Chih Hsu Tsuey-Ching Yang
author_sort	Yi-Wei Huang
title	Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
title_short	Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
title_full	Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
title_fullStr	Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
title_full_unstemmed	Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>
title_sort	impacts of penicillin binding protein 2 inactivation on β-lactamase expression and muropeptide profile in <italic toggle="yes">stenotrophomonas maltophilia</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/7ac2f3836eeb4544a167b104d831a375
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Impacts of Penicillin Binding Protein 2 Inactivation on β-Lactamase Expression and Muropeptide Profile in <italic toggle="yes">Stenotrophomonas maltophilia</italic>

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