The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria

ABSTRACT Members of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall compos...

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Autores principales:	Karin Schubert, Boris Sieger, Fabian Meyer, Giacomo Giacomelli, Kati Böhm, Angela Rieblinger, Laura Lindenthal, Nadja Sachs, Gerhard Wanner, Marc Bramkamp
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/20eaefdb682943f8a062af6d59aa6b64
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spelling	oai:doaj.org-article:20eaefdb682943f8a062af6d59aa6b642021-11-15T15:51:07ZThe Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria10.1128/mBio.02213-162150-7511https://doaj.org/article/20eaefdb682943f8a062af6d59aa6b642017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02213-16https://doaj.org/toc/2150-7511ABSTRACT Members of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall composition (mAGP) is conserved among all CMN group bacteria. The arabinogalactan and mycolic acid synthesis pathways constitute effective drug targets for tuberculosis treatment. Ethambutol (EMB), a classical antituberculosis drug, inhibits the synthesis of the arabinose polymer. Although EMB acts bacteriostatically, its underlying molecular mechanism remains unclear. Here, we used Corynebacterium glutamicum and Mycobacterium phlei as model organisms to study the effects of EMB at the single-cell level. Our results demonstrate that EMB specifically blocks apical cell wall synthesis, but not cell division, explaining the bacteriostatic effect of EMB. Furthermore, the data suggest that members of the family Corynebacterineae have two dedicated machineries for cell elongation (elongasome) and cytokinesis (divisome). IMPORTANCE Antibiotic treatment of bacterial pathogens has contributed enormously to the increase in human health. Despite the apparent importance of antibiotic treatment of bacterial infections, surprisingly little is known about the molecular functions of antibiotic actions in the bacterial cell. Here, we analyzed the molecular effects of ethambutol, a first-line antibiotic against infections caused by members of the genus Mycobacterium. We find that this drug selectively blocks apical cell growth but still allows for effective cytokinesis. As a consequence, cells survive ethambutol treatment and adopt a pneumococcal cell growth mode with cell wall synthesis only at the site of cell division. However, combined treatment of ethambutol and beta-lactam antibiotics acts synergistically and effectively stops cell proliferation.Karin SchubertBoris SiegerFabian MeyerGiacomo GiacomelliKati BöhmAngela RieblingerLaura LindenthalNadja SachsGerhard WannerMarc BramkampAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Karin Schubert Boris Sieger Fabian Meyer Giacomo Giacomelli Kati Böhm Angela Rieblinger Laura Lindenthal Nadja Sachs Gerhard Wanner Marc Bramkamp The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
description	ABSTRACT Members of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall composition (mAGP) is conserved among all CMN group bacteria. The arabinogalactan and mycolic acid synthesis pathways constitute effective drug targets for tuberculosis treatment. Ethambutol (EMB), a classical antituberculosis drug, inhibits the synthesis of the arabinose polymer. Although EMB acts bacteriostatically, its underlying molecular mechanism remains unclear. Here, we used Corynebacterium glutamicum and Mycobacterium phlei as model organisms to study the effects of EMB at the single-cell level. Our results demonstrate that EMB specifically blocks apical cell wall synthesis, but not cell division, explaining the bacteriostatic effect of EMB. Furthermore, the data suggest that members of the family Corynebacterineae have two dedicated machineries for cell elongation (elongasome) and cytokinesis (divisome). IMPORTANCE Antibiotic treatment of bacterial pathogens has contributed enormously to the increase in human health. Despite the apparent importance of antibiotic treatment of bacterial infections, surprisingly little is known about the molecular functions of antibiotic actions in the bacterial cell. Here, we analyzed the molecular effects of ethambutol, a first-line antibiotic against infections caused by members of the genus Mycobacterium. We find that this drug selectively blocks apical cell growth but still allows for effective cytokinesis. As a consequence, cells survive ethambutol treatment and adopt a pneumococcal cell growth mode with cell wall synthesis only at the site of cell division. However, combined treatment of ethambutol and beta-lactam antibiotics acts synergistically and effectively stops cell proliferation.
format	article
author	Karin Schubert Boris Sieger Fabian Meyer Giacomo Giacomelli Kati Böhm Angela Rieblinger Laura Lindenthal Nadja Sachs Gerhard Wanner Marc Bramkamp
author_facet	Karin Schubert Boris Sieger Fabian Meyer Giacomo Giacomelli Kati Böhm Angela Rieblinger Laura Lindenthal Nadja Sachs Gerhard Wanner Marc Bramkamp
author_sort	Karin Schubert
title	The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
title_short	The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
title_full	The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
title_fullStr	The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
title_full_unstemmed	The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria
title_sort	antituberculosis drug ethambutol selectively blocks apical growth in cmn group bacteria
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/20eaefdb682943f8a062af6d59aa6b64
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The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria

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