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C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

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C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus. / Paulowski, Laura; Beckham, Katherine S H; Johansen, Matt D; Berneking, Laura; Van, Nhi; Degefu, Yonatan; Staack, Sonja; Sotomayor, Flor Vasquez; Asar, Lucia; Rohde, Holger; Aldridge, Bree B; Aepfelbacher, Martin; Parret, Annabel; Wilmanns, Matthias; Kremer, Laurent; Combrink, Keith; Maurer, Florian P.

In: PNAS nexus, Vol. 1, No. 4, pgac130, 09.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2022, 'C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus', PNAS nexus, vol. 1, no. 4, pgac130. https://doi.org/10.1093/pnasnexus/pgac130

APA

Paulowski, L., Beckham, K. S. H., Johansen, M. D., Berneking, L., Van, N., Degefu, Y., Staack, S., Sotomayor, F. V., Asar, L., Rohde, H., Aldridge, B. B., Aepfelbacher, M., Parret, A., Wilmanns, M., Kremer, L., Combrink, K., & Maurer, F. P. (2022). C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus. PNAS nexus, 1(4), [pgac130]. https://doi.org/10.1093/pnasnexus/pgac130

Vancouver

Paulowski L, Beckham KSH, Johansen MD, Berneking L, Van N, Degefu Y et al. C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus. PNAS nexus. 2022 Sep;1(4). pgac130. https://doi.org/10.1093/pnasnexus/pgac130

Bibtex

@article{931c21f08986492eb47031fc375e6500,
title = "C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus",
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.",
author = "Laura Paulowski and Beckham, {Katherine S H} and Johansen, {Matt D} and Laura Berneking and Nhi Van and Yonatan Degefu and Sonja Staack and Sotomayor, {Flor Vasquez} and Lucia Asar and Holger Rohde and Aldridge, {Bree B} and Martin Aepfelbacher and Annabel Parret and Matthias Wilmanns and Laurent Kremer and Keith Combrink and Maurer, {Florian P}",
note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.",
year = "2022",
month = sep,
doi = "10.1093/pnasnexus/pgac130",
language = "English",
volume = "1",
journal = "PNAS nexus",
issn = "2752-6542",
publisher = "National Academy of Sciences",
number = "4",

}

RIS

TY - JOUR

T1 - C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

AU - Paulowski, Laura

AU - Beckham, Katherine S H

AU - Johansen, Matt D

AU - Berneking, Laura

AU - Van, Nhi

AU - Degefu, Yonatan

AU - Staack, Sonja

AU - Sotomayor, Flor Vasquez

AU - Asar, Lucia

AU - Rohde, Holger

AU - Aldridge, Bree B

AU - Aepfelbacher, Martin

AU - Parret, Annabel

AU - Wilmanns, Matthias

AU - Kremer, Laurent

AU - Combrink, Keith

AU - Maurer, Florian P

N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

U2 - 10.1093/pnasnexus/pgac130

DO - 10.1093/pnasnexus/pgac130

M3 - SCORING: Journal article

C2 - 36714853

VL - 1

JO - PNAS nexus

JF - PNAS nexus

SN - 2752-6542

IS - 4

M1 - pgac130

ER -