Pharmacodynamics of ClpP Activating Antibiotic Combinations against Gram-Positive Pathogens.

Pharmacodynamics of ClpP Activating Antibiotic Combinations against Gram-Positive Pathogens. Antimicrob Agents Chemother. 2019 Oct 14;: Authors: Mroue N, Arya A, Brown Gandt A, Russell C, Han A, Gavrish E, LaFleur M Abstract It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate the ClpP protease, killing high-density, non-dividing cultures of bacteria, tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug resistant Gram-positive pathogens in MIC assays with no pre-existing resistance detected. Killing of stationary phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant Enterococcus faecalis (VRE). None of the approved antibiot...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research