Synthesis of New DltA Inhibitors and Their Application as Adjuvant Antibiotics to Re‐Sensitize Methicillin Resistant Staphylococcus aureus

The synthesis of new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker and/or the amino-acid N-terminal moiety in order to increase in vivo stability and cell permeability. These new compounds were evaluated in vitro as DltA inhibitors and also in vivo as adjuvant antibiotics to re-sensitize methicillin resistant Staphylococcus aureus. Indeed, we showed that compounds 8, 9, 18, 27, 28, 35 and 36, containing modifications onto the carbohydrate or the linker, had moderate to excellent IC50 values. We also showed that 18 and 27 were able to efficiently re-sensitize MRSA to imipenem. Quantification of D-alanyl esters confirmed that these two compounds reduced the level of bacterial cell wall D-alanyl residues by 50% and 80%.