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

James Peek, Jiayi Xu, Han Wang, Shraddha Suryavanshi, Matthew Zimmerman, Riccardo Russo, Steven Park, David S. Perlin, Sean F. Brady

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2431-2440
Number of pages10
JournalACS infectious diseases
Volume6
Issue number9
DOIs
StatePublished - Sep 11 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

Keywords

  • Mycobacterium tuberculosis
  • Staphylococcus aureus
  • kanglemycin, antibiotic resistance
  • rifampicin
  • rifamycin

Fingerprint Dive into the research topics of 'A Semisynthetic Kanglemycin Shows in Vivo Efficacy against High-Burden Rifampicin Resistant Pathogens'. Together they form a unique fingerprint.

Cite this