(771b) Glucose-Derived Cationic Block Poly(beta-peptides) Reverse Intrinsic Antibiotic Resistance in Gram-Negative Pathogens

Authors: 
Si, Z., Nanyang Technological University
Lim, H. W., Nanyang Technological University
Keogh, D., nanyang Technological University
Feng, M. T. Y., NTU Food Technology Centre
Chen, Y., Nanyang Technological University
Chan-Park, M. B., Nanyang Technological University
Bazan, G. C., University of California, Santa Barbara
Greenberg, E. P., 8. Department of Microbiology, University of Washington (Seattle)
The rapid rise of multi-drug resistant (MDR) bacteria together with the decrease of effective antibiotics has been a mounting problem especially for pathogenic Gram-negative bacteria, since no new family of drug for the latter was found in the last past 50 years. Gram-negative bacteria possess intrinsic resistance to many antibiotics, particularly hydrophobic ones, because of the presence of the impermeable outer membrane which acts synergistically with their multi-drug efflux pumps to lead to high levels of multi-drug resistance in many pathogenic clinically relevant bacteria. The translation of the well-studied class of natural antimicrobial α-peptides to clinic use has been hampered by their relative toxicity and also their proteolytic instability. Herein, we have developed a novel glycosylated β-peptide series that is more proteolytically stable and acts as effective potentiating agents for several conventional antibiotics which Gram-negative bacteria are intrinsically resistant to. Our glycosylated cationic block β-peptides were synthesized through a one-step polymerization reaction due to the vastly differing reactivity of the monomers following by one-pot global deprotection. Our optimized glyco-β-peptide (named as PAS8-b-PDM12) acts synergistically with several antibiotics not commonly used for treating Gram-negative bacteria to reverse the intrinsic resistance of wild type Pseudomonas aeruginosa as well as various clinically relevant multi-drug resistant P. aeruginosa against these antibiotics. This is particularly significant since several recent reports show that P. aeruginosa has a highly impermeable outer membrane that eludes synergy effect of other combinations. We also found that the potentiating effect is broad spectrum towards various other Gram-negative bacteria including multi-drug resistant Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii with the MIC reduction factor ranging from 8 to 128 times decrease with 16µg/mL polymer addition. Also, in vivo synergistic effect was proven in a murine wound model. After 4h infection and 24 h treatment, the synergistic combination with rifampicin reached 99.5% eradiation against PAO1.