Antibacterial activity of THAM Trisphenylguanide against methicillin-resistant Staphylococcus aureus.
This study investigated the potential antibacterial activity of three series of compounds synthesized from 12 linear and branched polyamines with 2-8 amino groups, which were substituted to produce the corresponding guanides, biguanides, or phenylguanides, against Acinetobacter baumannii, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Antibacterial activity was measured for each compound by determining the minimum inhibitory concentration against the bacteria, and the toxicity towards mammalian cells was determined. The most effective compound, THAM trisphenylguanide, was studied in time-to-kill and cytoplasmic leakage assays against methicillin-resistant Staphylococcus aureus (MRSA, USA300) in comparison to chlorhexidine. Preliminary toxicity and MRSA challenge studies in mice were also conducted on this compound. THAM trisphenylguanide showed significant antibacterial activity (MIC ∼1 mg/L) and selectivity against MRSA relative to all the other bacteria examined. In time-to-kill assays it showed increased antimicrobial activity against MRSA versus chlorhexidine. It induced leakage of cytoplasmic content at concentrations that did not reduce cell viability, suggesting the mechanism of action may involve membrane disruption. Using an intraperitoneal mouse model of invasive MRSA disease, THAM trisphenylguanide reduced bacterial burden locally and in deeper tissues. This study has identified a novel guanide compound with selective microbicidal activity against Staphylococcus aureus, including a methicillin-resistant (MRSA) strain.
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Alan J
AJ
Weaver
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Joyce B
JB
Shepard
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America; Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
Royce A
RA
Wilkinson
Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
Robert L
RL
Watkins
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Sarah K
SK
Walton
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Amanda R
AR
Radke
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Thomas J
TJ
Wright
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Milat B
MB
Awel
Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
Catherine
C
Cooper
Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
Elizabeth
E
Erikson
Advanced BioDevices, Princeton, New Jersey, United States of America.
Mohamed E
ME
Labib
Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
Jovanka M
JM
Voyich
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Martin
M
Teintze
D040981:Acinetobacter baumannii / Q000187:drug effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001645:Biguanides / Q000737:chemistry* / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa
D000900:Anti-Bacterial Agents; D001645:Biguanides; D006146:Guanidines; C026943:phenylguanidine