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.
Abstract:
Polymyxins remain the last line treatment for multidrug-resistant (MDR) infections. As polymyxins resistance emerges, there is an urgent need to develop effective antimicrobial agents capable of mitigating MDR. Here, we report biodegradable guanidinium-functionalized polycarbonates with a distinctive mechanism that does not induce drug resistance. Unlike conventional antibiotics, repeated use of the polymers does not lead to drug resistance. Transcriptomic analysis of bacteria further supports development of resistance to antibiotics but not to the macromolecules after 30 treatments. Importantly, high in vivo treatment efficacy of the macromolecules is achieved in MDR A. baumannii-, E. coli-, K. pneumoniae-, methicillin-resistant S. aureus-, cecal ligation and puncture-induced polymicrobial peritonitis, and P. aeruginosa lung infection mouse models while remaining non-toxic (e.g., therapeutic index-ED50/LD50: 1473 for A. baumannii infection). These biodegradable synthetic macromolecules have been demonstrated to have broad spectrum in vivo antimicrobial activity, and have excellent potential as systemic antimicrobials against MDR infections.
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.
Related Concept Videos
Resistivity
Resistance
Equivalent Resistance
Resistance and Conductance
Various factors impact the resistance of a conductor. Spiraling in stranded conductors increases their...
Rolling Resistance
For instance, imagine a hard cylinder rolling on a comparatively soft surface. The cylinder's weight compresses the surface beneath it. As the cylinder moves, the material in front of it slows down due to...
Vascular Resistance
The primary determinants of vascular resistance are vessel diameter, blood viscosity, and vessel length. Among these, vessel diameter plays the most significant role due to the fourth power relationship described by...


