Abstract
Antibiotics save millions of lives every year. However, some bacteria have become resistant or even multi-resistant to these drugs, and there are already infections that are impossible to treat with the current therapeutic arsenal. Against this backdrop of a very serious threat to health, in 2017 the World Health Organization (WHO) published a list of bacteria classified according to the urgency with which new solutions must be found to eradicate them. To avoid falling into a "post-antibiotic era" where common infections become deadly again, it is therefore urgent to identify new drugs acting on new targets. Among the enzymes that need to be explored to combat microorganisms are those that are unstable and difficult to isolate, including certain metalloenzymes that could not previously be discovered due to a lack of knowledge and technology to characterize them.
GcpE (also known as "IspG") and LytB (or "IspH") are oxygen-sensitive enzymes essential to the survival of most bacteria, such as Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii (responsible for nosocomial diseases) and Mycobacterium tuberculosis (agent of tuberculosis). These two enzymes, absent in humans, catalyze the last two steps of the methylerythritol phosphate pathway, producing isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), the precursors essential for terpenoid synthesis. GcpE and LytB catalyze unconventional reactions using a [4Fe-4S]2+ center involved in two-electron transfer and water elimination. These reactions involving bioinorganic or even bioinorganometallic intermediates are a source of inspiration for the development of new antibacterial strategies. This seminar covered the discovery, characterization and breakthroughs achieved in elucidating the catalytic mechanism of these enzymes, as well as the exploitation of the initial results to design new, highly effective inhibitors.
