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

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.