<jats:title>Significance</jats:title> <jats:p>The shielding strategy for self-resistance in antibiotic biosynthesis from bacteria has been known to employ reversible group-transfer reactions that usually do not directly act on the antibiotic pharmacophore. Typically, the phosphorylation-modified, glycosylation-modified, acetylation-modified, and prepeptide-modified prodrug need to be activated by removing the protection group during or following export and, thereby, employing the hydrolysis reaction as the final step. Herein, we discover an unprecedented oxidative activation and overoxidative inactivation of a matured prodrug; significantly, the oxidation reaction directly deals with the drug warhead and occurs outside the host cells. This cryptic self-resistance mechanism sheds light on antibiotic resistance and the complex biology of extracellular environment.