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Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead.

ABSTRACT: Forgotten natural products offer value as antimicrobial scaffolds, providing diverse mechanisms of action that complement existing antibiotic classes. This study focuses on the derivatization of the cytotoxin blasticidin S, seeking to leverage its unique ribosome inhibition mechanism. Despite its complex zwitterionic properties, a selective protection and amidation strategy enabled the creation of a library of blasticidin S derivatives including the natural product P10. The amides exhibited significantly increased activity against Gram-positive bacteria and enhanced specificity for pathogenic bacteria over human cells. Molecular docking and computational property analysis suggested variable binding poses and indicated a potential correlation between cLogP values and activity. This work demonstrates how densely functionalized forgotten antimicrobials can be straightforwardly modified, enabling the further development of blasticidin S derivatives as lead compounds for a novel class of antibiotics.

SUBMITTER: Gannett C

PROVIDER: S-EPMC10945559 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead.

Gannett Cole C Tiller Kateland K Briganti Anthony J AJ Brown Anne M AM Weger-Lucarelli James J Lowell Andrew N AN

ACS medicinal chemistry letters 20240223 3

Forgotten natural products offer value as antimicrobial scaffolds, providing diverse mechanisms of action that complement existing antibiotic classes. This study focuses on the derivatization of the cytotoxin blasticidin S, seeking to leverage its unique ribosome inhibition mechanism. Despite its complex zwitterionic properties, a selective protection and amidation strategy enabled the creation of a library of blasticidin S derivatives including the natural product P10. The amides exhibited sign ...[more]

PMID: 38505852

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Project description:The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 μM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.

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Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead.

Publications

Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead.

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