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However, the clinical utility of rifamycins against <jats:italic>Mycobacterium abscessus<\/jats:italic> is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP\u2010ribosylation. Using a structure\u2010based approach, we rationally redesign rifamycins through strategic modification of the <jats:italic>ansa<\/jats:italic>\u2010chain to block ADP\u2010ribosylation while preserving on\u2010target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP\u2010ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. 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