Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins

Science. 2015 Jun 5;348(6239):1106-12. doi: 10.1126/science.aaa4690.

Abstract

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA-Directed DNA Polymerase
  • Disease Models, Animal
  • Drug Design
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Molecular Targeted Therapy*
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Peptides, Cyclic / therapeutic use
  • Protein Structure, Secondary
  • Streptomyces / chemistry
  • Streptomyces / drug effects
  • Streptomyces / metabolism
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Peptides, Cyclic
  • cyclohexylgriselimycin
  • griselimycin
  • methylgriselimycin
  • DNA-Directed DNA Polymerase
  • dnaN protein, Bacteria

Associated data

  • GENBANK/KP211414