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A Semisynthetic Kanglemycin Shows In Vivo Efficacy against High-Burden Rifampicin Resistant Pathogens

Authors
  • Peek, James1
  • Xu, Jiayi2
  • Wang, Han3
  • Suryavanshi, Shraddha4
  • Zimmerman, Matthew3
  • Russo, Riccardo4
  • Park, Steven3
  • Perlin, David S.3
  • Brady, Sean F.1
  • 1 The Rockefeller University, United States , (United States)
  • 2 Belfer Research Building, United States , (United States)
  • 3 Hackensack Meridian Health, United States , (United States)
  • 4 Rutgers, The State University of New Jersey, United States , (United States)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Aug 10, 2020
Volume
6
Issue
9
Pages
2431–2440
Identifiers
DOI: 10.1021/acsinfecdis.0c00223
PMID: 32786275
PMCID: PMC7497472
Source
PubMed Central
Keywords
License
Unknown

Abstract

Semisynthetic rifamycin derivatives such as rifampicin (Rif) are first line treatments for tuberculosis and other bacterial infections. Historically, synthetic modifications made to the C-3/C-4 region of the rifamycin naphthalene core, like those seen in Rif, have yielded the biggest improvements in pharmacological properties. However, modifications found in natural product rifamycin congeners occur at other positions in the structure. The kanglemycins (Kangs) are a family of rifamycin congeners with a unique collection of natural modifications including a dimethylsuccinic acid appended to their polyketide backbone. These modifications confer activity against the single most common clinically relevant Rif resistance (RifR) mutation in the antibiotic’s target, the bacterial RNA polymerase (RNAP). Here we evaluate the in vivo efficacy of Kang A, the parent compound in the Kang family, in a murine model of bacterial peritonitis/sepsis. We then set out to improve its potency by combining its natural tailoring modifications with semisynthetic derivatizations at either its acid moiety or in the C-3/C-4 region. A collection of C-3/C-4 benzoxazino Kang derivatives exhibit improved activity against wild-type bacteria, and acquire activity against the second most common clinically relevant RifR mutation. The semisynthetic analogue 3′-hydroxy-5′-[4-isobutyl-1-piperazinyl] benzoxazino Kang A (Kang KZ) protected mice against infection with either Rif sensitive MRSA or a highly virulent RifR Staphylococcus  aureus strain in a neutropenic peritonitis/sepsis model and led to reduced bacterial burdens. The compounds generated in this study may represent promising candidates for treating RifR infections.

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