A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance

Willy Chin1,2, Guansheng Zhong3, Qinqin Pu4

  • 1Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, Singapore.

Nature Communications
|March 4, 2018
PubMed

Insights

New biodegradable polymers offer a potent solution against multidrug-resistant infections. These novel macromolecules demonstrate broad-spectrum efficacy without inducing bacterial resistance, unlike traditional antibiotics.

Area of Science:

  • Polymer Chemistry
  • Antimicrobial Research
  • Infectious Diseases

Background:

  • Polymyxins are critical last-resort treatments for multidrug-resistant (MDR) infections.
  • Emerging resistance to polymyxins necessitates the development of novel antimicrobial strategies.
  • Existing antibiotics face challenges with resistance development, limiting their long-term effectiveness.

Purpose of the Study:

  • To develop and evaluate biodegradable guanidinium-functionalized polycarbonates as novel antimicrobial agents.
  • To investigate the mechanism of action and resistance profile of these synthetic macromolecules.
  • To assess the in vivo efficacy and safety of these compounds against MDR bacterial infections.

Main Methods:

  • Synthesis of biodegradable guanidinium-functionalized polycarbonates.
  • Assessment of bacterial resistance development through repeated treatments and transcriptomic analysis.
  • In vivo efficacy testing in multiple mouse models of MDR bacterial infections (A. baumannii, E. coli, K. pneumoniae, MRSA, P. aeruginosa) and polymicrobial peritonitis.
  • Toxicology assessment to determine therapeutic index.

Main Results:

  • The synthesized polycarbonates exhibit a unique mechanism of action that does not induce bacterial resistance, even after repeated exposure.
  • Transcriptomic analysis confirmed resistance development to conventional antibiotics but not to the macromolecules.
  • Significant in vivo efficacy was demonstrated across various MDR bacterial infections and polymicrobial peritonitis models.
  • The compounds exhibited a high therapeutic index, indicating a favorable safety profile (e.g., therapeutic index of 1473 for A. baumannii infection).

Conclusions:

  • Biodegradable guanidinium-functionalized polycarbonates represent a promising new class of antimicrobial agents.
  • These macromolecules offer broad-spectrum activity against MDR infections with a low propensity for resistance development.
  • Their favorable efficacy and safety profile make them strong candidates for systemic treatment of challenging bacterial infections.

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