C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.

Paulowski, L; Beckham, KSH; Johansen, MD; Berneking, L; Van, N; Degefu, Y; Staack, S; Sotomayor, FV; Asar, L; Rohde, H; Aldridge, BB; Aepfelbacher, M; Parret, A; Wilmanns, M; Kremer, L; Combrink, K; Maurer, FP

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.

Paulowski, L Beckham, KSH Johansen, MD Berneking, L Van, N Degefu, Y Staack, S Sotomayor, FV Asar, L Rohde, H Aldridge, BB Aepfelbacher, M Parret, A Wilmanns, M Kremer, L Combrink, K Maurer, FP

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Publisher:: Oxford University Press (OUP)
Publication Type:: Journal Article
Citation:: PNAS Nexus, 2022, 1, (4), pp. pgac130
Issue Date:: 2022-09

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Field	Value	Language
dc.contributor.author	Paulowski, L
dc.contributor.author	Beckham, KSH
dc.contributor.author	Johansen, MD
dc.contributor.author	Berneking, L
dc.contributor.author	Van, N
dc.contributor.author	Degefu, Y
dc.contributor.author	Staack, S
dc.contributor.author	Sotomayor, FV
dc.contributor.author	Asar, L
dc.contributor.author	Rohde, H
dc.contributor.author	Aldridge, BB
dc.contributor.author	Aepfelbacher, M
dc.contributor.author	Parret, A
dc.contributor.author	Wilmanns, M
dc.contributor.author	Kremer, L
dc.contributor.author	Combrink, K
dc.contributor.author	Maurer, FP
dc.contributor.editor	Nelson, KE
dc.date.accessioned	2023-02-14T00:29:22Z
dc.date.available	2022-08-05
dc.date.available	2023-02-14T00:29:22Z
dc.date.issued	2022-09
dc.identifier.citation	PNAS Nexus, 2022, 1, (4), pp. pgac130
dc.identifier.issn	2752-6542
dc.identifier.issn	2752-6542
dc.identifier.uri	http://hdl.handle.net/10453/166090
dc.description.abstract	Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	Oxford University Press (OUP)
dc.relation.ispartof	PNAS Nexus
dc.relation.isbasedon	10.1093/pnasnexus/pgac130
dc.rights	info:eu-repo/semantics/openAccess
dc.title	C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.
dc.type	Journal Article
utslib.citation.volume	1
utslib.location.activity	England
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
dc.date.updated	2023-02-14T00:29:16Z
pubs.issue	4
pubs.publication-status	Published online
pubs.volume	1
utslib.citation.issue	4

Abstract:

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

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http://hdl.handle.net/10453/166090