Restoring Methicillin-Resistant Staphylococcus aureus Susceptibility to β-Lactam Antibiotics

Abstract

Methicillin-resistant Staphylococcus aureus infection can be treated effectively by combining a β-lactam antibiotic with a drug that targets FtsZ.

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

“…. The yellow-colored molecule is PC190723, which is located at the interdomain cleft between H7 helix and C-terminal domain (PDB entry 4DXD) [25].…”

“…The t 1/2 of TXA707 following intravenous administration of TXA709 was 3.65 h, while the t 1/2 of PC190723 following the intravenous administration of TXA541 was 0.56 h. TXA709 thus displayed better pharmacokinetic properties by keeping its strong antibacterial activity and its efficacy in vivo. In a study of the mice model infected with MRSA ATCC 33591, a 2-log reduction in bacterial CFU can be found in the model treated with 120 or 160 mg kg −1 of TXA709 administered orally, while only about 0.5-log reduction was found when orally administered 200 mg kg −1 of PC190723 [25,97]. …”

“…reported that a truncated version of CRAMP (GEKLKKIGQKIKNFFQKL, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] exhibited antibacterial activity and FtsZ inhibitory effects [122]. This peptide can totally inhibit the growth of B. subtilis and E. coli at concentration of 20 μM and 50 μM, respectively.…”

“…One possible reason is that the structural information on FtsZ co-crystals with inhibitors is still insufficient. Although more than 30 crystal structures of FtsZ have been collected in the Protein Data Bank, around 30 % of them are from S. aureus, and only PC 190723 and its analogs have the co-complex with S. aureus FtsZ [25,125], which provides limited information on how FtsZ inhibitors interact with FtsZ and affect the FtsZ function. PC190723 locates in the interdomain cleft between C-terminal and H7 helix of FtsZ in a flat orientation and performs to stabilize the FtsZ assembly by shifting the H7 helix.…”

Exposing a chink in the armor of methicillin-resistant Staphylococcus aureus

“…However, the robustness of the MRSA phenotype is modulated by many other aspects of the MSSA strain background that acquires mecA (6). The complexity of the MRSA phenotype thus offers hope that drug interactions and other interventions can be devised that will allow the restoration of an MSSA phenotype to MRSA strains (7)(8)(9). The work of Brown et al (4) identifies a significant target that may be exploited to allow resensitization of MRSA.…”