Impact of Genomics-Emerging Targets for Antibacterial Therapy

Barrett, John

doi:10.1016/b0-08-045044-x/00225-x

Cited by 3 publications

(2 citation statements)

References 130 publications

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“…The discovery of novel antibacterial classes has proven particularly challenging for the research community in both industry and academia in the last few decades . The onset of the genomic era and the promise of the discovery of novel mechanisms have not translated into marketed drugs . The need for new antibiotics to treat drug-resistant Gram-positive infections is acute, especially against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium and Enterococcus faecalis .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

Martínez-Botella

Breen

Duffy³

et al. 2012

J. Med. Chem.

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Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

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Section: Introductionmentioning

confidence: 99%

Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)

Martínez-Botella

Breen

Duffy³

et al. 2012

J. Med. Chem.

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“…Rather than optimizing existing classes of antibacterial agents, an alternative avenue to pursue new drugs is to seek out targets that have not been used previously in antibacterial therapy, as this approach avoids cross-resistance on the compound level as well as the target level. Advancements in genomics, high-throughput screening of compound libraries, and structure-based design have allowed the exploration of many novel targets for antibacterial therapy (7,8,9). One of the targets explored was 4=-phosphopantetheine adenylyltransferase (PPAT) (8,10).…”

mentioning

confidence: 99%

Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

Jonge

Walkup

Lahiri

et al. 2013

Antimicrob Agents Chemother

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Inhibitors of 4=-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy.

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