Mitomycin Resistance in Streptomyces lavendulae Includes a Novel Drug-Binding-Protein-Dependent Export System

Abstract

Sequence analysis of Streptomyces lavendulae NRRL 2564 chromosomal DNA adjacent to the mitomycin resistance locusmrd (encoding a previously described mitomycin-binding protein [P. Sheldon, D. A. Johnson, P. R. August, H.-W. Liu, and D. H. Sherman, J. Bacteriol. 179:1796–1804, 1997]) revealed a putative mitomycin C (MC) transport gene (mct) encoding a hydrophobic polypeptide that has significant amino acid sequence similarity with several actinomycete antibiotic export proteins. Disruption of mct by insertional inactivation resulted in an S. lavendulae mutant strain that was considerably more sensitive to MC. Expression of mct in Escherichia coli conferred a fivefold increase in cellular resistance to MC, led to the synthesis of a membrane-associated protein, and correlated with reduced intracellular accumulation of the drug. Coexpression ofmct and mrd in E. coli resulted in a 150-fold increase in resistance, as well as reduced intracellular accumulation of MC. Taken together, these data provide evidence that MRD and Mct function as components of a novel drug export system specific to the mitomycins.

Characterization of a novel DNA glycosylase fromS. sahachiroiinvolved in the reduction and repair of azinomycin B induced DNA damage

“…The important antitumor antibiotic mitomycin C is produced by Streptomyces lavendulae as an inert prodrug that requires enzymatic or chemical reduction to generate a highly effective alkylating agent. Mitomycin self-resistance occurs via three cellular mechanisms: a flavoenzyme (McrA) that oxidizes the active reduced form of mitomycin C ( 14 ), a drug binding protein (Mrd) that prevents reductive activation of the prodrug and a membrane-associated protein (Mct) involved in drug efflux ( 15 , 16 ).…”

Self‐Resistance to an Antitumor Antibiotic: A DNA Glycosylase Triggers the Base‐Excision Repair System in Yatakemycin Biosynthesis

“…This is the first example of a DNA glycosylase involved in the self‐resistance to a DNA‐targeting antibiotic 3. 4, 20 Currently, the biological functions, structure, and mechanistic features of mammalian DNA glycosylases are being pursued, and several studies showed that DNA glycosylases confound cancer alkylation therapy by excising cytotoxic N3‐methyladenine bases formed by DNA‐targeting anticancer compounds 21. Since YTM is a potent antitumor agent, the functional and structural elucidation of YtkR2 would help to understand the mechanism of this DNA‐alkylating chemotherapy.…”

Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens

“…Each bleomycin-family producer member has one or more genes related to ABC transporters in their biosynthesis clusters ( Du et al, 2000 ; Tao et al, 2007 ; Galm et al, 2009 ), which may be used to remove the antibiotics bound to binding proteins. For additional examples, see references ( Sheldon et al, 1997 , 1999 ; Pozzi et al, 2016 ).…”