Discovery of antimicrobial molecules related to bacterial cell wall formation
Abstract
Bacterial resistance to antibiotics is a pressing, worldwide problem, and the 'drug development void' of the last several years has permitted that major human pathogens become resistant to all antibiotics, including 'last resort molecules'. This reality demands a multi-disciplinary effort towards the exploration of new ideas that could lead to the development of treatments that explore yet untapped sources and target key bacterial processes that are essential for bacterial survival. At the LNBio, one of my group's recent interests has been the screening for new, potential antibiotics in libraries of natural products prepared from the Brazilian biodiversity, a vast, totally novel, yet untapped source of antimicrobials. An initial screening campaign performed at the LNBio identified >30 original samples that block the action of Penicillin-Binding Proteins (PBPs), key bacterial cell wall biosynthesis enzymes, as well as growth of both Gram-negative and Gram-positive bacteria. In addition, thanks to support from FAPESP, we structurally characterized the first complex between a PBP and a partner molecule that assures bacterial cell wall elongation, which represents an initial glimpse into new interfaces that can be targeted with small molecules viewing novel antibiotic development. The present grant application views the expansion of these very exciting results through the characterization of higher order cell wall biosynthesis complexes as well as the continuation of the effort of identification of new natural product inhibitors of antibiotic-resistance systems. This is a high risk, high gain project that combines state-of-the-art structural biology with microbiology and biophysics, and will impact both biology and public health. ANTIBIO-BAC thus consolidates efforts to study different aspects of bacterial cell wall biogenesis and drug resistance in order to understand molecular interactions that play key roles in bacterial survival and virulence, and identify unique molecules that can lead to novel antibiotherapies. (AU)