Towards the site-selective modification of aminoglycoside antibiotics and their biological evaluation

The increase of antibiotic resistance together with the gap in the discovery of new antibiotics is an alarming problem. An increase of mortality worldwide caused by antimicrobial resistance has been estimated by 2050. Hence, actions need to be taken now to minimize this important problem. Among the different strategies, the chemical diversification of clinically used antibiotics is a powerful approach to accelerate the discovery of new efficient antibiotics. During my Ph.D., we aimed to modify aminoglycoside antibiotics, such as paromomycin and kanamycin, by inducing catalytic-driven regioselective oxidation at the C3 position of the glucose-configured residue, as previously developed in our group. In this way, a 3-keto-sugar is obtained which can undergo several chemical modifications leading to modified aminoglycosides. From this, we wished to synthesize derivatives that could overcome the resistance induced by phosphoryl transferase enzymes (APH3’) and maintain a good antibiotic potency. The synthesized aminoglycoside derivatives have been tested on several E.coli strains containing different subtypes of the gene coding for APH3’ to determine their effectiveness towards bacterial strains expressing the resistant enzyme. Next to this, cell-free translation assays have been performed to gain information on whether the newly synthesized aminoglycoside derivatives maintain the targeting activity for their parental compounds. Additional studies such as co-crystallization with a clinical relevant resistant isoenzyme and biochemical assays have also been investigated to determine the efficiency of the modification in avoiding the resistance mechanism at the enzymatic level. The results of the synthetic approaches and the biological/biochemical assays are reported in this thesis