Novel promising Linezolid analogues: rational design and biological evaluation

The rising incidence of multidrug resistance in Gram-positive pathogen bacteria represents one of the most significant challenge for scientific communities worldwide. Linezolid, an oxazolidinone antibiotic, is highly effective for treatment of serious infections caused by Gram-positive pathogens resistant to other antibiotics including meticillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant S. pneumonia. Linezolid has a unique mechanism of action which targets protein synthesis. Unfortunately, the emergence of Linezolid-resistant of MRSA and other bacteria has already been observed highlighting the need for finding novel oxazolidinone-type drugs with improved potency. In our study we describe the design, the synthesis and biological evaluation of previously unreported Linezolid analogues bearing the urea and thiourea functionality at the C-5 position. We used a computational approach in order to find new derivatives with improved activity. We have found a Linezolid analogoue showing good anti-microbial activity. This compound is effective against S. aureus, also meticillin-resistant, vancomycin-resistant enterococci and penicillin-resistant S. pneumonia. To understand the mechanism of action of this analogue, resistant mutants of S. aureus were generated. They contain mutations in the L3 gene coding for the L3 riboprotein.