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, Jahrgang 1, Nr. 4, pgac130, 09.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -