Unlocking the enigma of phenotypic drug tolerance: Mechanisms and emerging therapeutic strategies

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Alok K Mishra1, Ritesh P Thakare1, Bela G Santani2

  • 1Division of Microbiology, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Lucknow, Uttar Pradesh, 226031, India; Department of Molecular Cell and Cancer Biology, UMass Chan Medical School, Worcester, MA, 01605, USA.

Biochimie
|January 3, 2024
PubMed

Insights

Microbial drug tolerance, a non-genetic survival strategy, complicates antimicrobial resistance. Understanding persistence mechanisms is key to developing new therapies for chronic and refractory infections.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Infectious Diseases

Background:

  • Antimicrobial resistance (AMR) is a major global health threat.
  • Phenotypic drug tolerance, distinct from genetic resistance, allows microbes to survive antibiotic exposure without mutations.
  • Persistence mechanisms are crucial for chronic and recurrent infections.

Purpose of the Study:

  • To comprehensively review microbial phenotypic drug tolerance and persister formation.
  • To explore the role of tolerance in acquired drug resistance.
  • To highlight emerging therapeutic strategies against persistent bacterial infections.

Main Methods:

  • Literature review of microbial persistence mechanisms.
  • Analysis of molecular pathways involved in drug tolerance.
  • Examination of therapeutic interventions for refractory infections.

Main Results:

  • Microbial populations utilize diverse strategies like dormancy, biofilms, and L-forms to achieve drug tolerance.
  • Key molecular mechanisms include toxin-antitoxin systems, oxidative stress responses, altered metabolism, and (p)ppGpp signaling.
  • Understanding these mechanisms is vital for predicting treatment outcomes and designing novel therapies.

Conclusions:

  • Phenotypic drug tolerance is a significant challenge in combating antimicrobial resistance.
  • Targeting persistence mechanisms offers a promising avenue for treating chronic and difficult-to-eradicate bacterial infections.
  • Further research into innovative therapeutic approaches is essential to overcome persistent bacterial infections.
Keywords:
(p)ppGpp-signalingBedaquilinBiofilm-formationDrug-toleranceL-form-bacteriaToxin-antitoxin

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