Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>

ABSTRACT Clostridium difficile is the causative agent of the deadly C. difficile infection. Resistance of the pathogen to β-lactam antibiotics plays a major role in the development of the disease, but the mechanism of resistance is currently unknown. We discovered that C. difficile encodes class D β...

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Autores principales:	Marta Toth, Nichole K. Stewart, Clyde Smith, Sergei B. Vakulenko
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Clostridium difficile antibiotic resistance beta-lactamases Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8081a353a6874a4090b4509fee48d0d5
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spelling	oai:doaj.org-article:8081a353a6874a4090b4509fee48d0d52021-11-15T15:52:18ZIntrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>10.1128/mBio.01803-182150-7511https://doaj.org/article/8081a353a6874a4090b4509fee48d0d52018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01803-18https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile is the causative agent of the deadly C. difficile infection. Resistance of the pathogen to β-lactam antibiotics plays a major role in the development of the disease, but the mechanism of resistance is currently unknown. We discovered that C. difficile encodes class D β-lactamases, i.e., CDDs, which are intrinsic to this species. We studied two CDD enzymes, CDD-1 and CDD-2, and showed that they display broad-spectrum, high catalytic efficiency against various β-lactam antibiotics, including penicillins and expanded-spectrum cephalosporins. We demonstrated that the cdd genes are poorly expressed under the control of their own promoters and contribute only partially to the observed resistance to β-lactams. However, when the cdd1 gene was expressed under the control of efficient promoters in the antibiotic-sensitive Clostridium cochlearium strain, it produced high-level resistance to β-lactams. Taken together, the results determined in this work demonstrate the existence in C. difficile of intrinsic class D β-lactamases which constitute a reservoir of highly potent enzymes capable of conferring broad-spectrum, clinically relevant levels of resistance to β-lactam antibiotics. This discovery is a significant contribution to elucidation of the mechanism(s) of resistance of the clinically important pathogen C. difficile to β-lactam antibiotics. IMPORTANCE C. difficile is a spore-forming anaerobic bacterium which causes infection of the large intestine with high mortality rates. The C. difficile infection is difficult to prevent and treat, as the pathogen is resistant to many antimicrobial agents. Prolonged use of β-lactam antibiotics for treatment of various infectious diseases triggers the infection, as these drugs suppress the abundance of protective gut bacteria, allowing the resistant C. difficile bacteria to multiply. While resistance of C. difficile to β-lactam antibiotics plays the major role in the development of the disease, the mechanism of resistance is unknown. The significance of our research is in the discovery in C. difficile of β-lactamases, enzymes that destroy β-lactam antibiotics. These findings ultimately can help to combat deadly C. difficile infections.Marta TothNichole K. StewartClyde SmithSergei B. VakulenkoAmerican Society for MicrobiologyarticleClostridium difficileantibiotic resistancebeta-lactamasesMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile antibiotic resistance beta-lactamases Microbiology QR1-502
spellingShingle	Clostridium difficile antibiotic resistance beta-lactamases Microbiology QR1-502 Marta Toth Nichole K. Stewart Clyde Smith Sergei B. Vakulenko Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
description	ABSTRACT Clostridium difficile is the causative agent of the deadly C. difficile infection. Resistance of the pathogen to β-lactam antibiotics plays a major role in the development of the disease, but the mechanism of resistance is currently unknown. We discovered that C. difficile encodes class D β-lactamases, i.e., CDDs, which are intrinsic to this species. We studied two CDD enzymes, CDD-1 and CDD-2, and showed that they display broad-spectrum, high catalytic efficiency against various β-lactam antibiotics, including penicillins and expanded-spectrum cephalosporins. We demonstrated that the cdd genes are poorly expressed under the control of their own promoters and contribute only partially to the observed resistance to β-lactams. However, when the cdd1 gene was expressed under the control of efficient promoters in the antibiotic-sensitive Clostridium cochlearium strain, it produced high-level resistance to β-lactams. Taken together, the results determined in this work demonstrate the existence in C. difficile of intrinsic class D β-lactamases which constitute a reservoir of highly potent enzymes capable of conferring broad-spectrum, clinically relevant levels of resistance to β-lactam antibiotics. This discovery is a significant contribution to elucidation of the mechanism(s) of resistance of the clinically important pathogen C. difficile to β-lactam antibiotics. IMPORTANCE C. difficile is a spore-forming anaerobic bacterium which causes infection of the large intestine with high mortality rates. The C. difficile infection is difficult to prevent and treat, as the pathogen is resistant to many antimicrobial agents. Prolonged use of β-lactam antibiotics for treatment of various infectious diseases triggers the infection, as these drugs suppress the abundance of protective gut bacteria, allowing the resistant C. difficile bacteria to multiply. While resistance of C. difficile to β-lactam antibiotics plays the major role in the development of the disease, the mechanism of resistance is unknown. The significance of our research is in the discovery in C. difficile of β-lactamases, enzymes that destroy β-lactam antibiotics. These findings ultimately can help to combat deadly C. difficile infections.
format	article
author	Marta Toth Nichole K. Stewart Clyde Smith Sergei B. Vakulenko
author_facet	Marta Toth Nichole K. Stewart Clyde Smith Sergei B. Vakulenko
author_sort	Marta Toth
title	Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
title_short	Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
title_full	Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
title_fullStr	Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
title_full_unstemmed	Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>
title_sort	intrinsic class d β-lactamases of <italic toggle="yes">clostridium difficile</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/8081a353a6874a4090b4509fee48d0d5
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Intrinsic Class D β-Lactamases of <italic toggle="yes">Clostridium difficile</italic>

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