The effect of FtsZ inhibitors on the B-lactam resistant activity in methicillin-resistant staphylococcus aureus

Abstract

The rapid emergence of antibiotic resistance in bacteria urges the need of new drugs to fight against bacterial infections caused by pathogenic microbes. The FtsZ protein is an essential cytoskeleton element involved in most bacterial cell divisions and has been shown to be a promising drug target. Previous studies indicated that derivatives of 3­methoxybenzamide (3-MBA) are inhibitors of the FtsZ protein and they can effectively inhibit the growth of Gram-positive rod-shaped Bacillus subtilis (B. subtilis) and exhibit synergistic effects when used in combination with ß-lactams. The aims of this project are to determine the antibacterial activities of 3-MBA derived FtsZ inhibitors (F332 and PC190723) and their combinations with ß-lactams against methicillin-resistant Staphylococcus aureus (MRSA). 3-MBA derived FtsZ inhibitors were found to possess excellent growth inhibition effect on MRSA when used alone, and synergistically when used together with ß-lactams. The bactericidal effects of individual and combinations of FtsZ inhibitors and ß-lactams reveal that FtsZ inhibitors can restore the bactericidal and bacteriolysis activities of ß-lactams against MRSA. Delocalization of FtsZ protein as well as newly grown lipid-linked peptidoglycan precursor from their normal position were observed in S. aureus when it was treated with FtsZ inhibitors and in combination with ß-lactams. Treatment by a combination of FtsZ inhibitor and ß-lactam also caused cell enlargement of S. aureus which is a well-known physiological change when FtsZ activity is being interfered. It is believed that this change is related to a decrease in peptidoglycan crosslinking resulting from the delocalization of lipid-linked peptidoglycan precursors over the entire cell.