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It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad\u2010spectrum antibiotic lead was generated with significantly improved activity, including against all Gram\u2010negative pathogens of the ESKAPE panel. 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