Teicoplanin Reprogrammed with the N-Acyl-Glucosamine Pharmacophore at the Penultimate Residue of Aglycone Acquires Broad-Spectrum Antimicrobial Activities Effectively Killing Gram-Positive and -Negative Pathogens

Lipoglycopeptide antibiotics, for example, teicoplanin (Tei) and A40926, are more potent than vancomycin against Gram-positive (Gram-(+)) drug-resistant pathogens, for example, methicillin-resistant Staphylococcus aureus (MRSA). To extend their therapeutic effectiveness on vancomycin-resistant S. aureus (VRSA), the biosynthetic pathway of the N-acyl glucosamine (Glc) pharmacophore at residue 4 (r4) of teicoplanin pseudoaglycone redirection to residue 6 (r6) was attempted. On the basis of crystal structures, two regioselective biocatalysts Orf2*T (a triple-mutation mutant S98A/V121A/F193Y) and Orf11*S (a single-mutation mutant W163A) were engineered, allowing them to act on GlcNAc at r6. New analogs thereby made show marked antimicrobial activity against MRSA and VRSA by 2–3 orders of magnitude better than teicoplanin and vancomycin. The lipid side chain of the Tei-analogs armed with a terminal mono- or diguanidino group extends the antimicrobial specificity from Gram-(+) to Gram-negative (Gram-(−)), compa...