A Widespread Glycosidase Confers Lobophorin Resistance and Host‐Dependent Structural Diversity

Structural diversification of lobophorins (LOBs) in S. coelicolor M1154/pCSG5560 through glycosylation, deglycosylation and reglycosylation was unexpectedly found to be correlated with cross-talk between the endogenous glycosidase KijX and the products encoded by the exogenous lob BGC. KijX homologues are widespread among bacteria, archaea and fungi, and encode the same glycohydrolytic activity on LOBs as a resistance mechanism to detoxify LOBs.

Abstract

Identifying new environmental resistance determinants is significant to combat rising antibiotic resistance. Herein we report the unexpected correlation of a lobophorin (LOB) resistance-related glycosidase KijX with the host-dependent chemical diversity of LOBs, by a process of glycosylation, deglycosylation and reglycosylation. KijX homologues are widespread among bacteria, archaea and fungi, and encode the same glycohydrolytic activity on LOBs. The crystal structure of AcvX (a KijX homologue) shows a similar fold to that of the glycoside hydrolase family 113 and a special negatively charged groove to accommodate and deglycosylate LOBs. Antagonistic assays indicate kijX as a defense weapon of actinomycetes to combat LOB producers in environment, reflecting an elegant coevolution relationship. Our study provides insight into the KijX-related glycosidases as preexisting resistance determinants and represents an example of resistance genes accidentally integrated into natural product assembly.

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