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Natural compounds continue to serve as the most fruitful source of new antimicrobials. Analysis of bacterial genomes have revealed that the biosynthetic potential of antibiotic producers by far exceeds the number of already discovered structures. However, due to the repeated discovery of known substances, it has become necessary to change both approaches to the search for antibiotics and the sources of producer strains. The pressure of natural selection and the diversity of interactions in symbiotic communities make animal microbiomes promising sources of novel substances. Here, microorganisms associated with various animals were examined in terms of their antimicrobial agents. The application of alternative cultivation techniques, ultrahigh-throughput screening, and genomic analysis facilitated the investigation of compounds produced by unique representatives of the animal microbiota. We believe that new strategies of antipathogen defense will be discovered by precisely studying cell–cell and host–microbe interactions in microbiomes in the wild. [ABSTRACT FROM AUTHOR]

A synthetic approach towards rearranged angucyclinones related to Elmenols A and B and their synthetic derivatives has been developed. Carbon skeleton is constructed in a straightforward manner by directed o‐lithiation of m‐anisaldehyde dimethyl acetal and its further nucleophilic addition to properly substituted naphthalene carbaldehydes. The latter can be achieved via several alternative synthetic schemes, the most efficient of them are discussed herein. [ABSTRACT FROM AUTHOR]

The discovery of antibiotics was one of the fundamental stages in the development of humanity, leading to a dramatic increase in the life expectancy of millions of people all over the world. The uncontrolled use of antibiotics resulted in the selection of resistant strains of bacteria, limiting the effectiveness of antimicrobial therapy nowadays. Antimicrobial peptides (AMPs) were considered promising candidates for next-generation antibiotics for a long time. However, the practical application of AMPs is restricted by their low therapeutic indices, impaired pharmacokinetics, and pharmacodynamics, which is predetermined by their peptide structure. Nevertheless, the DNA-encoded nature of AMPs enables creating broad repertoires of artificial biodiversity of antibiotics, making them versatile templates for the directed evolution of antibiotic activity. Lantibiotics are a unique class of AMPs with an expanded chemical space. A variety of post-translational modifications, mechanisms of action on bacterial membranes, and DNA-encoded nature make them a convenient molecular template for creating highly representative libraries of antimicrobial compounds. Isolation of new drug candidates from this synthetic biodiversity is extremely attractive but requires high-throughput screening of antibiotic activity. The combination of synthetic biology and ultrahigh-throughput microfluidics allows implementing the concept of directed evolution of lantibiotics for accelerated creation of new promising drug candidates. [ABSTRACT FROM AUTHOR]

The article offers information about the kinase-mediated phosphorylation which represents strategies for the emergence of antibiotic resistance. It mentions that nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. It explores that crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation.

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. [ABSTRACT FROM AUTHOR]