A novel kinase provides self-resistance to isocoumarin antibiotic amicoumacin A in Bacillus

Nazarov, A.; Terekhov, S.; Smirnov, I.; Gabibov, A.

Авторы: Nazarov A., Terekhov S., Smirnov I., Gabibov A.
Журнал: FEBS open bio
Номер: 11
Год издания: 2021
Издательство: John Wiley & Sons Inc.
Местоположение издательства: United States
Первая страница: 367
DOI: 10.1002/2211-5463.13205
Аннотация: The increasing number of infection cases caused by antibiotic-re-sistant strains of pathogens challenges the scientiﬁc communityto discover new antibiotics. This calls for the application of newplatforms for antibiotic activity screening. We developed theinnovative microﬂuidic platform for ultrahigh-throughput screen-ing allowing deep functional proﬁling of bacterial communities.This platform was applied for efﬁcient isolation of microorgan-isms displaying antibacterial activity. We discovered that the oralmicrobiome of the East Siberian brown bear contains a popula-tion of Bacillus pumilus strains inhibiting the growth of commonhuman pathogen S. aureus. The genome mining revealed a newbiosynthetic gene cluster of antibiotic amicoumacin A (Ami)responsible for the anti-S. aureus activity of these strains. Herewe performed the exhaustive proteomic and metabolomic analy-sis of B. pumilus associated with the activation of Ami produc-tion. These data display dramatic differences in protein levels ofAmiA-AmiM biosynthetic enzymes described previously, as wellas unknown putative kinase AmiN and phosphatase AmiO. Weobserved a rapid phosphorylation of Ami by puriﬁed AmiNkinase in vitro, while puriﬁed AmiO demonstrated phosphataseactivity toward phosphorylated Ami. In turn, the phosphoryla-tion resulted in a more than 400-fold decrease in the antibacterialactivity of Ami. The biological function of AmiN was furtherelucidated using E. coli BL21(DE3) and B. subtilis 168 DyerIstrains. The heterological expression of amiN provided the resis-tance of model microorganisms toward Ami. We found that theAmi cluster is present only in a few B. pumilus reference gen-omes, while the presence of amiN and its homologs is almostubiquitous among Bacillus. We believe that AmiN and its homo-logs are particularly important for the ecology of these bacteriaand their survival in the wild. This work is supported by RFBRgrant 19-14-00331.
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A novel kinase provides self-resistance to isocoumarin antibiotic amicoumacin A in Bacillusстатья Тезисы

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