Crossroads of Antibiotic Resistance and Biosynthesis

J Mol Biol. 2019 Aug 23;431(18):3370-3399. doi: 10.1016/j.jmb.2019.06.033. Epub 2019 Jul 6.


The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The origins of clinically relevant antibiotic resistance genes found in human pathogens have been traced to ancient microbial producers of antibiotics in natural environments. Widespread and frequent antibiotic use amplifies environmental pools of antibiotic resistance genes and increases the likelihood for the selection of a resistance event in human pathogens. This perspective will provide an overview of the origins of antibiotic resistance to highlight the crossroads of antibiotic biosynthesis and producer self-protection that result in clinically relevant resistance mechanisms. Some case studies of synergistic antibiotic combinations, adjuvants, and hybrid antibiotics will also be presented to show how native antibiotic producers manage the emergence of antibiotic resistance.

Keywords: adjuvant; antibiotic resistance; combination therapy; hybrid antibiotics; natural product biosynthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects
  • Bacteria / genetics
  • Biological Evolution
  • Biological Products / metabolism
  • Biological Products / pharmacology
  • Carrier Proteins
  • Drug Combinations
  • Drug Discovery
  • Drug Resistance, Microbial / drug effects*
  • Drug Resistance, Microbial / genetics
  • Drug Resistance, Microbial / physiology
  • Drug Synergism
  • Environment
  • Humans
  • Kinetics
  • Metagenomics
  • Thermodynamics


  • Anti-Bacterial Agents
  • Biological Products
  • Carrier Proteins
  • Drug Combinations