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Going on offense against the gram-negative defense [Microbiology]

Bacterial infections resistant to antibiotics are becoming more common, posing a significant health risk (1). The CDC and WHO have identified gram-negative drug-resistant pathogens as being particularly dangerous, and such infections are resistant to nearly all available antibiotics in some cases (2, 3). The most concerning of these infections are three classes of nonfastidious gram-negative pathogens, Enterobacteriaceae (including Escherichia coli and Klebsiella pneumonia ), Pseudomonas aeruginosa , and Acinetobacter baumannii . As only nine classes of antibiotics (that engage five targets) are available for the treatment of these infections (4), the need for new classes of antibiotics effective against gram-negative bacteria is self-evident. In PNAS, Zhang et al. (5) present an innovative approach for discovering antibiotics that exploit previously untargeted components of lipopolysaccharide (LPS) biogenesis and use this screening platform to identify a lead compound that inhibits LPS biosynthetic machinery. Historically, there has been a heavy reliance on whole-cell toxicity assays for identification of new antibiotic classes, and, in fact, all classes of US Food and Drug Administration-approved antibiotics were initially discovered in these types of cell culture phenotypic screens (1). Unfortunately, this approach has rarely provided compelling lead compounds with activity against gram-negative bacteria; the quinolones are the most recently introduced class of broad-spectrum antibiotics, over 50 y ago (in 1968) (4). AstraZeneca, GlaxoSmithKline, and others have all published detailed accounts of their independent screening of a combined >8 million compounds in bacterial cell culture death assays; it is sobering to note that these experiments failed to produce any compounds with sufficient gram-negative activity to merit advancement (6⇓⇓–9). While biochemical … [↵][1]1To whom correspondence should be addressed. Email: hergenro{at}illinois.edu. [1]: #xref-corresp-1-1

Authors:   Bryon S. Drown; Paul J. Hergenrother
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   26
Year:   2018
Pages:   6530
DOI:   10.1073/pnas.1807278115
Publication date:   26-Jun-2018
Facts, background information, dossiers
  • quinolones
  • lipopolysaccharide
  • Klebsiella
  • infections
  • GlaxoSmithKline
  • food
  • AstraZeneca
  • assays
  • Acinetobacter baumannii
More about Proceedings of the National Academy of Sciences
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