Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens.
Erica N. Parker,Bryon S. Drown,Emily J. Geddes,Hyang Yeon Lee,Nahed Ismail,Gee W. Lau,Paul J. Hergenrother +6 more
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TLDR
This work provides tools for the facile discovery and development of high-accumulating compounds in E. coli, and a general blueprint for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.Abstract:
Gram-negative bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-negative bacteria1-7. Here, we report the development of a web application-eNTRyway-that predicts compound accumulation (in Escherichia coli) from its structure. In conjunction with structure-activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452-a Gram-positive-only antibiotic8-into versions that accumulate in E. coli and possess antibacterial activity against high-priority Gram-negative pathogens. The lead compound Debio-1452-NH3 operates as an antibiotic via the same mechanism as Debio-1452, namely potent inhibition of the enoyl-acyl carrier protein reductase FabI, as validated by in vitro enzyme assays and the generation of bacterial isolates with spontaneous target mutations. Debio-1452-NH3 is well tolerated in vivo, reduces bacterial burden in mice and rescues mice from lethal infections with clinical isolates of Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. This work provides tools for the facile discovery and development of high-accumulating compounds in E. coli, and a general blueprint for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.read more
Citations
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The Science of Antibiotic Discovery.
TL;DR: The emerging platform is based on understanding the rules that guide the permeation of molecules into bacteria and on advances in microbiology, which enable us to identify and access attractive groups of secondary metabolite producers, and will enable reliable production of lead compounds to combat AMR.
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Biology of antimicrobial resistance and approaches to combat it
TL;DR: This Review summarizes recent advances and continuing limitations in the understanding of AMR and suggests approaches for combating its clinical consequences, including identification of previously unexploited bacterial targets, new antimicrobial compounds, and improved combination drug regimens.
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Defining new chemical space for drug penetration into Gram-negative bacteria.
Shibin Zhao,Justyna W. Adamiak,Vincent Bonifay,Jitender Mehla,Helen I. Zgurskaya,Derek S. Tan +5 more
TL;DR: An overview of emerging insights into the difficulty of antibiotic discovery posed by the double-membrane cell envelope of Gram-negative bacteria and active drug efflux requires better understanding of bacterial permeability and compound accumulation, and more diverse chemical libraries.
Journal ArticleDOI
Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance.
Craig R. MacNair,Eric D. Brown +1 more
TL;DR: It is demonstrated that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants and is a high priority approach for further development.
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Recent advances in antibacterial agents.
Qidi Kong,Yushe Yang +1 more
TL;DR: In this paper, a review summarizes these advances and provides perspective on future directions of antibacterial agents, including new compounds of known classes and new compounds with new mechanisms, and summarizes the recent advances in the antibacterial area.
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