C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

Author:

Paulowski Laura1ORCID,Beckham Katherine S H2,Johansen Matt D3ORCID,Berneking Laura4,Van Nhi5,Degefu Yonatan5,Staack Sonja2,Sotomayor Flor Vasquez14ORCID,Asar Lucia4,Rohde Holger4,Aldridge Bree B5ORCID,Aepfelbacher Martin4,Parret Annabel26,Wilmanns Matthias27ORCID,Kremer Laurent38ORCID,Combrink Keith910,Maurer Florian P1411ORCID

Affiliation:

1. National and WHO Supranational Reference Center for Mycobacteria, Research Center Borstel, Leibniz Lung Center , 23845 Borstel, Germany

2. European Molecular Biology Laboratory , 22607 Hamburg, Germany

3. Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier , 34293 Montpellier, France

4. Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf , 20246 Hamburg, Germany

5. Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance , Boston, MA 02111, USA

6. Charles River Laboratories , 2340 Beerse, Belgium

7. University Medical Center Hamburg-Eppendorf , 20246 Hamburg, Germany

8. INSERM, Institut de Recherche en Infectiologie de Montpellier , 34293 Montpellier, France

9. Department of Chemistry and Biochemistry, Texas A&M International University , Laredo, TX 77843, USA

10. Department of Chemistry, Blinn College , Bryan Campus, Brenham, TX 77833, USA

11. German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems , 23845 Borstel, Germany

Abstract

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.

Funder

Universität Hamburg

Publisher

Oxford University Press (OUP)

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3