Modelling for Aminoglycoside Design and Development – MADD

The clinical importance of antibiotics remains beyond question. However, their over- and mis-uses have created a strong selective pressure on bacteria, which induced the emergence of (multi)resistant strains. Antibioresistance is becoming so pregnant that since 2017, the World Health Organization (WHO) lists bacteria threatening most human health (AWaRe, ESKAPEE lists), and those for which new antibiotics are urgently needed. In this context, aminoglycosides (AG) are among the first discovered and still investigated antibiotics due to their broad-spectrum antibacterial activity. AGs are indeed proven to kill a wide range of aerobic Gram negative and positive bacteria but their clinical use is partly hampered by the apparition of resistances to bacteria (mostly AG-modifying enzymes-AME) and by its nephro- and oto-toxicities. To overcome most of their drawbacks, we are involved in an interdisciplinary consortium gathering three partners, offering a unique combination of strictly complementary skills with experts in chemistry, computer aided-design, and microbiology that will synergize to identify new efficient AGs. The MADD project aims at developing tobramycin and amikacin derivatives with reduced toxicity and lower sensitivity to AMEs while preserving antibiotic activity. The design will be supported by molecular model of the identified AMEs with the parent AGs and their derivatives.