TY - JOUR
T1 - C1-CBP-vancomycin
T2 - Impact of a Vancomycin C-Terminus Trimethylammonium Cation on Pharmacological Properties and Insights into Its Newly Introduced Mechanism of Action
AU - Wu, Zhi Chen
AU - Isley, Nicholas A.
AU - Okano, Akinori
AU - Weiss, William J.
AU - Boger, Dale L.
N1 - Funding Information:
We gratefully acknowledge financial support from the NIH (CA041101 to D.L.B.), an NIH postdoctoral fellowship (F32 GM114948 to N.A.I.), and a JITRI-Scripps Fellowship (Z.-C.W.). We especially acknowledge and thank the Concept Acceleration Program (CAP) within The National Institute of Allergy and Infectious Diseases (NIAID), Division of Microbiology and Infectious Diseases, and especially Dr. Ann Eakin for sponsoring and organizing the contract services used for the studies that were performed at the University of North Texas (tolerability, PK), by Eurofins Panlabs (PHH cytotoxicity, protein binding, permeability, microsomal metabolic stability, CYP inhibition), or by Pharmacology Discovery Services Taiwan, Ltd., a partner lab of Eurofins Pharma Discovery Services (efficacy).
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/2/7
Y1 - 2020/2/7
N2 - C1-CBP-vancomycin (3) was examined alongside CBP-vancomycin for susceptibility to acquired resistance upon serial exposure against two vancomycin-resistant enterococci strains where its activity proved more durable and remarkably better than many current therapies. Combined with earlier studies, this observation confirmed an added mechanism of action was introduced by incorporation of the trimethylammonium cation and that C1-CBP-vancomycin exhibits activity against vancomycin-resistant organisms through two synergistic mechanisms of action, both independent of d-Ala-d-Ala/d-Lac binding. New insights into this added mechanism of action, induced cell membrane permeabilization, can be inferred from studies that show added exogenous lipoteichoic acid reduces antimicrobial activity, rescues bacteria cell growth inhibition, and blocks induced cell permeabilization properties of C1-CBP-vancomycin, suggesting a direct binding interaction with embedded teichoic acid is responsible for the added mechanism of action and enhanced antimicrobial activity. Further studies indicate that the trimethylammonium cation does not introduce new liabilities in common pharmacological properties of the analogue and established that 3 is well tolerated in mice, displays substantial PK improvements over both vancomycin and CBP-vancomycin, and exhibits in vivo efficacy against a challenging multidrug-resistant and vancomycin-resistant S. aureus strain that is representative of the resistant pathogens all fear will emerge in the general population.
AB - C1-CBP-vancomycin (3) was examined alongside CBP-vancomycin for susceptibility to acquired resistance upon serial exposure against two vancomycin-resistant enterococci strains where its activity proved more durable and remarkably better than many current therapies. Combined with earlier studies, this observation confirmed an added mechanism of action was introduced by incorporation of the trimethylammonium cation and that C1-CBP-vancomycin exhibits activity against vancomycin-resistant organisms through two synergistic mechanisms of action, both independent of d-Ala-d-Ala/d-Lac binding. New insights into this added mechanism of action, induced cell membrane permeabilization, can be inferred from studies that show added exogenous lipoteichoic acid reduces antimicrobial activity, rescues bacteria cell growth inhibition, and blocks induced cell permeabilization properties of C1-CBP-vancomycin, suggesting a direct binding interaction with embedded teichoic acid is responsible for the added mechanism of action and enhanced antimicrobial activity. Further studies indicate that the trimethylammonium cation does not introduce new liabilities in common pharmacological properties of the analogue and established that 3 is well tolerated in mice, displays substantial PK improvements over both vancomycin and CBP-vancomycin, and exhibits in vivo efficacy against a challenging multidrug-resistant and vancomycin-resistant S. aureus strain that is representative of the resistant pathogens all fear will emerge in the general population.
UR - http://www.scopus.com/inward/record.url?scp=85074582729&partnerID=8YFLogxK
U2 - 10.1021/acs.joc.9b02314
DO - 10.1021/acs.joc.9b02314
M3 - Article
C2 - 31670958
AN - SCOPUS:85074582729
SN - 0022-3263
VL - 85
SP - 1365
EP - 1375
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 3
ER -