Fragment-based drug design of a bacterial kinase inhibitor capable of increasing the antibiotic sensitivity of clinical isolates.

According to the World Health Organization (WHO), antimicrobial resistance is a serious global health issue. Overcoming antibiotic resistance involves several strategies, including the inhibition of resistance mechanisms. Among the various resistance mechanisms, aminoglycoside phosphotransferases (APHs) catalyze the transfer of the γ-phosphate from a nucleotide donor to various aminoglycosides, leading to their inactivation. In this work, using a fragment-based drug design (FBDD) approach, we have identified and characterized a promising APH inhibitor capable of increasing the sensitivity of Pseudomonas aeruginosa and Staphylococcus aureus resistant to aminoglycosides. It is therefore a good candidate for the future development of APH inhibitors to be prescribed in combination with aminoglycosides. This molecule is a competitive inhibitor of adenosine 5'-triphosphate (ATP), the phosphate donor of APHs. Further studies are required to optimize this molecule to improve its specificity for APHs and its bioavailability in bacteria.