ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets

Bacterial antibiotic resistance is rapidly growing globally and poses a severe health threat as the number of multidrug resistant (MDR) and extensively drug-resistant (XDR) bacteria increases. The observed resistance is partially due to natural evolution and to a large extent is attributed to antibiotic misuse and overuse. As the rate of antibiotic resistance increases, it is crucial to develop new drugs to address the emergence of MDR and XDR pathogens. A variety of strategies are employed to address issues pertaining to bacterial antibiotic resistance and these strategies include: (1) the anti-virulence approach, which ultimately targets virulence factors instead of killing the bacterium, (2) employing antimicrobial peptides that target key proteins for bacterial survival and, (3) phage therapy, which uses bacteriophages to treat infectious diseases. In this review, we take a renewed look at a group of ESKAPE pathogens which are known to cause nosocomial infections and are able to escape the bactericidal actions of antibiotics by reducing the efficacy of several known antibiotics. We discuss previously observed escape mechanisms and new possible therapeutic measures to combat these pathogens and further suggest caseinolytic proteins (Clp) as possible therapeutic targets to combat ESKAPE pathogens. These proteins have displayed unmatched significance in bacterial growth, viability and virulence upon chronic infection and under stressful conditions. Furthermore, several studies have showed promising results with targeting Clp proteins in bacterial species, such as Mycobacterium tuberculosis, Staphylococcus aureus and Bacillus subtilis.