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Article

Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
2
Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia
3
Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow 127051, Russia
4
Federal Research and Clinical Centre of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
5
Department of Life Sciences, Higher School of Economics, Moscow 101000, Russia
*
Authors to whom correspondence should be addressed.
Academic Editor: Jorge H. Leitão
Received: 12 March 2020 / Revised: 25 March 2020 / Accepted: 30 March 2020 / Published: 2 April 2020
The global spread of antibiotic resistance is forcing the scientific community to find new molecular strategies to counteract it. Deep functional profiling of microbiomes provides an alternative source for the discovery of novel antibiotic producers and probiotics. Recently, we implemented this ultrahigh-throughput screening approach for the isolation of Bacillus pumilus strains efficiently producing the ribosome-targeting antibiotic amicoumacin A (Ami). Proteomics and metabolomics revealed essential insight into the activation of Ami biosynthesis. Here, we applied omics to boost Ami biosynthesis, providing the optimized cultivation conditions for high-scale production of Ami. Ami displayed a pronounced activity against Lactobacillales and Staphylococcaceae, including methicillin-resistant Staphylococcus aureus (MRSA) strains, which was determined using both classical and massive single-cell microfluidic assays. However, the practical application of Ami is limited by its high cytotoxicity and particularly low stability. The former is associated with its self-lactonization, serving as an improvised intermediate state of Ami hydrolysis. This intramolecular reaction decreases Ami half-life at physiological conditions to less than 2 h, which is unprecedented for a terminal amide. While we speculate that the instability of Ami is essential for Bacillus ecology, we believe that its stable analogs represent attractive lead compounds both for antibiotic discovery and for anticancer drug development. View Full-Text
Keywords: deep functional profiling; ultrahigh-throughput screening; amicoumacin; antibiotic activity spectrum; amide stability toward hydrolysis; single-cell; multi-omics deep functional profiling; ultrahigh-throughput screening; amicoumacin; antibiotic activity spectrum; amide stability toward hydrolysis; single-cell; multi-omics
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MDPI and ACS Style

Terekhov, S.S.; Nazarov, A.S.; Mokrushina, Y.A.; Baranova, M.N.; Potapova, N.A.; Malakhova, M.V.; Ilina, E.N.; Smirnov, I.V.; Gabibov, A.G. Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin. Antibiotics 2020, 9, 157. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040157

AMA Style

Terekhov SS, Nazarov AS, Mokrushina YA, Baranova MN, Potapova NA, Malakhova MV, Ilina EN, Smirnov IV, Gabibov AG. Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin. Antibiotics. 2020; 9(4):157. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040157

Chicago/Turabian Style

Terekhov, Stanislav S., Anton S. Nazarov, Yuliana A. Mokrushina, Margarita N. Baranova, Nadezhda A. Potapova, Maja V. Malakhova, Elena N. Ilina, Ivan V. Smirnov, and Alexander G. Gabibov 2020. "Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin" Antibiotics 9, no. 4: 157. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040157

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