AUTHOR=Weber Lea , Hagemann Anna , Kaltenhäuser Jila , Besser Manuela , Rockenfeller Patrick , Ehrhardt Anja , Stuermer Ewa , Bachmann Hagen Sjard 

TITLE=Bacteria Are New Targets for Inhibitors of Human Farnesyltransferase

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.628283

DOI=10.3389/fmicb.2021.628283

ISSN=1664-302X

ABSTRACT=<p>Farnesyltransferase inhibitors (FTIs) are focus for the treatment of several diseases, particularly in the field of cancer therapy. Their potential, however, goes even further, as a number of studies have evaluated FTIs for the treatment of infectious diseases such as malaria, African sleeping sickness, leishmaniosis, and hepatitis D virus infection. Little is known about protein prenylation mechanisms in human pathogens. However, disruption of <italic>IspA</italic>, a gene encoding the geranyltranstransferase of <italic>Staphylococcus aureus</italic> (<italic>S. aureus</italic>) leads to reprogramming of cellular behavior as well as impaired growth and decreased resistance to cell wall-targeting antibiotics. We used an agar well diffusion assay and a time kill assay and determined the minimum inhibitory concentrations of the FTIs lonafarnib and tipifarnib. Additionally, we conducted cell viability assays. We aimed to characterize the effect of these FTIs on <italic>S. aureus</italic>, methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA), <italic>Staphylococcus epidermidis</italic> (<italic>S. epidermidis</italic>), <italic>Escherichia coli</italic> (<italic>E. coli</italic>), <italic>Enterococcus faecium</italic> (<italic>E. faecium</italic>), <italic>Klebsiella pneumoniae</italic> (<italic>K. pneumoniae</italic>), <italic>Pseudomonas aeruginosa</italic> (<italic>P. aeruginosa</italic>), and <italic>Streptococcus pneumoniae</italic> (<italic>S. pneumoniae</italic>). Both the FTIs lonafarnib and tipifarnib were capable of inhibiting the growth of the Gram-positive bacteria <italic>S. aureus</italic>, MRSA, <italic>S. epidermidis</italic>, and <italic>S. pneumoniae</italic>, whereas no effect was observed on Gram-negative bacteria. The analysis of the impact of lonafarnib and tipifarnib on common human pathogens might lead to novel insights into their defense mechanisms and therefore provide new therapeutic targets for antibiotic-resistant bacterial infections.</p>