TY - JOUR
T1 - A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance
AU - Martin, James K.
AU - Sheehan, Joseph P.
AU - Bratton, Benjamin P.
AU - Moore, Gabriel M.
AU - Mateus, André
AU - Li, Sophia Hsin Jung
AU - Kim, Hahn
AU - Rabinowitz, Joshua D.
AU - Typas, Athanasios
AU - Savitski, Mikhail M.
AU - Wilson, Maxwell Z.
AU - Gitai, Zemer
N1 - Funding Information:
The B. subtilis CRISPR knockdown library was a kind gift from Jason M. Peters. Flow cytometry was performed in collaboration with Christina DeCoste (Princeton University Flow Cytometry Resource Facility [FCRF]). We appreciate the support and feedback from lab members in the Gitai and Shaevitz labs. Funding was provided in part by NIH ( DP1AI124669 to Z.G., J.P.S., B.P.B., and J.K.M. and T32 GM007388 to J.K.M. and G.M.M.), as well as Princeton DFR Innovation Funds for New Ideas in Science (to J.K.M. and J.P.S.). Additional funding provided by the National Science Foundation ( NSF PHY-1734030 to B.P.B.) and for the FCRF by the National Cancer Institute ( NCI-CCSG P30CA072720-5921 ). The opinions, findings, and conclusions or recommendations expressed in this material contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the National Science Foundation.
Funding Information:
The B. subtilis CRISPR knockdown library was a kind gift from Jason M. Peters. Flow cytometry was performed in collaboration with Christina DeCoste (Princeton University Flow Cytometry Resource Facility [FCRF]). We appreciate the support and feedback from lab members in the Gitai and Shaevitz labs. Funding was provided in part by NIH (DP1AI124669 to Z.G. J.P.S. B.P.B. and J.K.M. and T32 GM007388 to J.K.M. and G.M.M.), as well as Princeton DFR Innovation Funds for New Ideas in Science (to J.K.M. and J.P.S.). Additional funding provided by the National Science Foundation (NSF PHY-1734030 to B.P.B.) and for the FCRF by the National Cancer Institute (NCI-CCSG P30CA072720-5921). The opinions, findings, and conclusions or recommendations expressed in this material contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the National Science Foundation. Conceptualization, Z.G. J.K.M. M.Z.W. and H.K.; Methodology, Z.G. B.P.B. M.Z.W. A.M. A.T. M.M.S. J.R. S.H.-J.L. and H.K.; Software, M.Z.W. J.K.M. B.P.B. A.T. and M.M.S.; Validation, J.P.S.; Formal Analysis, B.P.B. and G.M.M.; Investigation, M.Z.W. J.K.M. J.P.S. G.M.M. A.M. A.T. M.M.S. S.H.-J.L. and B.P.B.; Resources, J.P.S. and M.Z.W.; Writing – Original Draft, Z.G. and J.K.M.; Writing – Reviewing & Editing, Z.G. B.P.B. J.P.S. H.K. and C.D.; Visualization, J.P.S. J.K.M. and B.P.B.; Supervision, Z.G. H.K. J.R. A.T. and M.M.S.; Funding Acquisition, Z.G. J.R. A.T. and M.M.S. A patent application describing the use of SCH-79797 as an antibiotic, as well as the pharmaceutical composition and use as antibiotic of derivatives is currently pending.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6/25
Y1 - 2020/6/25
N2 - The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.
AB - The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.
KW - Acinetobacter baumannii
KW - Gram-negative pathogens
KW - Neisseria gonorrhoeae
KW - antibiotics
KW - broad spectrum
KW - dual-target drugs
KW - folate metabolism
KW - membrane disrupting
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U2 - 10.1016/j.cell.2020.05.005
DO - 10.1016/j.cell.2020.05.005
M3 - Article
C2 - 32497502
AN - SCOPUS:85086510595
SN - 0092-8674
VL - 181
SP - 1518-1532.e14
JO - Cell
JF - Cell
IS - 7
ER -