Abstract
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.
Highlights
Ever since antibiotics were introduced into clinical practice, bacterial pathogens have been developing resistance which reduces or eliminates their effectiveness
Antibacterial Activity In vitro We initially screened all the guanide, biguanide, and phenylguanide compounds we had synthesized, and their parent amines, in a bacterial viability assay against three Gram- negative
There were no significant differences between Minimum inhibitory concentration (MIC) and Minimum bactericidal concentrations (MBC) for each S. aureus strain and no significant differences between the two S. aureus strains using 2-tailed unpaired T-tests (p.0.05, n$7). doi:10.1371/journal.pone.0097742.t002
Summary
Ever since antibiotics were introduced into clinical practice, bacterial pathogens have been developing resistance which reduces or eliminates their effectiveness. Opportunistic pathogens with innate resistance to antibiotics have become emerging problems, in hospital settings. In developed countries, such as the United States, bacterial species that have acquired multiple drug resistance include the ESKAPE pathogens, aptly named for their ability to escape the effects of our current antimicrobial drugs. These include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species [1]. MRSA have become resistant to the multiple classes of antibiotics including beta lactams, macrolides, and quinolones [2], as well as the glycopeptide vancomycin, the common drug of last resort [3]
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