Abstract
The worldwide emergence of antibiotic resistance poses a serious threat to human health. A molecular understanding of resistance strategies employed by bacteria is obligatory to generate less-susceptible antibiotics. Albicidin is a highly potent antibacterial compound synthesized by the plant-pathogenic bacterium Xanthomonas albilineans. The drug-binding protein AlbA confers albicidin resistance to Klebsiella oxytoca. Here we show that AlbA binds albicidin with low nanomolar affinity resulting in full inhibition of its antibacterial activity. We report on the crystal structure of the drug-binding domain of AlbA (AlbAS) in complex with albicidin. Both α-helical repeat domains of AlbAS are required to cooperatively clamp albicidin, which is unusual for drug-binding proteins of the MerR family. Structure-guided NMR binding studies employing synthetic albicidin derivatives give valuable information about ligand promiscuity of AlbAS. Our findings thus expand the general understanding of antibiotic resistance mechanisms and support current drug-design efforts directed at more effective albicidin analogs.
Highlights
The worldwide emergence of antibiotic resistance poses a serious threat to human health
Albicidin is bactericidal in the nanomolar range against Gram-positive and in particular against Gram-negative bacteria with low minimal inhibitory concentrations (MIC), e.g., against Staphylococcus aureus (4.0 μg mL−1), Salmonella enteritidis (0.5 μg mL−1), Pseudomonas aeruginosa DSM 117 (1.0 μg mL−1), and Escherichia coli (0.063 μg mL−1)[3,4]
Another strategy that counteracts the antibacterial effect of albicidin is drug binding, as it is known for the tetracycline-binding protein (TetR family)[15] or the thiostreptonbinding protein (MerR family)[16]
Summary
The worldwide emergence of antibiotic resistance poses a serious threat to human health. A number of resistance mechanisms against albicidin have been described: examples include the nucleoside transporter Tsx, for which mutations have been reported that compromise its abilities to import albicidin[11,12], or the endopeptidase AlbD from Pantoea dispersa[13], which cleaves albicidin into two inactive fragments[14] Another strategy that counteracts the antibacterial effect of albicidin is drug binding, as it is known for the tetracycline-binding protein (TetR family)[15] or the thiostreptonbinding protein (MerR family)[16]. The MerR (Mercury Resistance) transcriptional regulator family is known to activate several multi-drug resistance (MDR) systems in response to environmental stress[21] Members of this family are characterized by a highly conserved N-terminal winged helix-turn-helix (HTH) DNA-binding motif. Our findings represent valuable knowledge about antibiotic capture as an important resistance mechanism and how to possibly circumvent it in the case of albicidin
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