Bacterial Infections are an important and emerging global healthcare issue. ?-Lactam antibiotics, one of the most important developments in modern medicine, have saved millions of lives and continue to serve as the major therapy to treat bacterial infections. The highly reactive four- membered ?-lactam ring is the key structure for dictating efficacy of this class of antibiotics. Unfortunately, bacteria are rapidly developing resistance to one or more of the most frequently used antibiotics. ?-Lactamase production and excretion is a major defense mechanism employed by several drug-resistant bacterial pathogens. For example, nearly 30% of hospital- acquired infections are identified as methicillin-resistant Staphylococcus aureus (MRSA) strains that are resistant to penicillin, methicillin and many other ?-lactam antibiotics, leading to serious infection problems for patients. Currently, vancomycin and amoxicillin/clavulanic acid are among the most commonly used antibiotics for the treatment of Gram-positive bacterial infections. Although these antibiotics are among the strongest of their classes, the high frequency use has resulted in their decreased susceptibility. Efficient antibiotics and/or antimicrobial agents are in high demand, but have limited success in fighting bacterial resistance. We discover a class of charged metallopolymers that exhibits synergistic effects against multidrug resistant bacteria by effectively lysing bacterial cells and efficiently disarming activity of ?-lactamases. Various conventional ?-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin and cefazolin, are protected from ?-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic metallopolymers. There are at least three innovations involved in this project: (1) our approaches effectively prevent bacterial resistance by protecting and reinstating antibiotics; (2) more importantly our metallopolymer platforms eliminate the possibility of recurrence of bacterial resistance via disarming ?- lactamases and disrupting cell membranes; (3) these metallopolymers are non- or minimally cytotoxic for mammalian cells. Our research and discoveries could provide a new pathway to designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug resistant bacteria and superbugs.

Public Health Relevance

The ever-increasing emergence of bacteria resistance to traditional antibiotics is a puzzling issue in battling infectious diseases. We propose to develop new paradigm of metallopolymers to reinstate vitality of conventional antibiotics. The proposed research will have a significant impact on advancing the development of novel antimicrobial agents for the success of bacteria- associated infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI120987-03
Application #
9378085
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Xu, Zuoyu
Project Start
2015-11-01
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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