Targeting virulence not viability in the search for future antibacterials

Heras, Begoña; Scanlon, M.J.; Martin, Jennifer L.

doi:10.1111/bcp.12356

Cited by 152 publications

(151 citation statements)

References 77 publications

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“…3 It has been hypothesized that antivirulence therapies will be effective when used alone, in combination therapy with traditional antibiotics, or as a prophylactic treatment. 2,3,7 …”

Section: Introductionmentioning

confidence: 99%

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

2017

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Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure–activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor’s amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.

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“…3 It has been hypothesized that antivirulence therapies will be effective when used alone, in combination therapy with traditional antibiotics, or as a prophylactic treatment. 2,3,7 …”

Section: Introductionmentioning

confidence: 99%

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

2017

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“…The current economic loss of preventable hospital-acquired infections ($5.7-6.7 billion) is now comparable to the costs of stroke ($6.7 billion), diabetes mellitus ($4.5 billion), and chronic obstructive lung disease ($4.2 billion) in the United States (69). Anti-virulence therapy is an attractive strategy to combat rapidly spreading infections caused by multidrug-resistant A. baumannii (28,70,71).…”

Section: Discussionmentioning

confidence: 99%

“…Deletion or mutation of dsbA attenuates virulence factor maturation in bacterial pathogens including Proteus mirabilis (22), uropathogenic Escherichia coli (23), Burkholderia pseudomallei (24), Vibrio cholerae (25), Shigella flexneri (26), and Salmonella enterica serovar typhimurium (27). DsbA inhibitors are potential anti-virulence drugs (28).…”

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confidence: 99%

Structure of the Acinetobacter baumannii Dithiol Oxidase DsbA Bound to Elongation Factor EF-Tu Reveals a Novel Protein Interaction Site

Premkumar

Kurth

Duprez

et al. 2014

Journal of Biological Chemistry

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Background: DsbA is a master virulence determinant of bacterial pathogens and a target for antivirulence drugs. Results: AbDsbA is a class I dithiol oxidase that binds EF-Tu-derived and DsbB-derived peptides on different enzyme surfaces. Conclusion: Discovery of high affinity peptide interaction sites provides a platform for inhibitor design. Significance: AbDsbA inhibitors could have anti-biofilm activity against multidrug resistant Acinetobacter baumannii.

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“…Pathogen-specific antibiotics that target only one or a small set of species are also receiving increased interest, with fidaxomicin being recently approved as a selective agent for C. difficile that permits the gut microbiome to recover. 74,94 Other strategies for fighting bacterial infections, such as targeting virulence 3,95,96 or treatment with antibodies or phage, 56,97 are alternatives to growth-suppressive, small molecule antibiotics that spare the microbiome and possibly slow resistance. However, these approaches must be demonstrated to cure patients as effectively as traditional antibiotics or they will not gain FDA approval, let alone find clinical utility.…”

Section: Narrow-spectrum Antibioticsmentioning

confidence: 99%

Targeted treatment for bacterial infections: prospects for pathogen-specific antibiotics coupled with rapid diagnostics

Maxson

Mitchell

2016

Tetrahedron

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Antibiotics are a cornerstone of modern medicine and have significantly reduced the burden of infectious diseases. However, commonly used broad-spectrum antibiotics can cause major collateral damage to the human microbiome, causing complications ranging from antibiotic-associated colitis to the rapid spread of resistance. Employing narrower spectrum antibiotics targeting specific pathogens may alleviate this predicament as well as provide additional tools to expand an antibiotic repertoire threatened by the inevitability of resistance. Improvements in clinical diagnosis will be required to effectively utilize pathogen-specific antibiotics and new molecular diagnostics are poised to fulfill this need. Here we review recent trends and the future prospects of deploying narrower spectrum antibiotics coupled with rapid diagnostics. Further, we discuss the theoretical advantages and limitations of this emerging approach to controlling bacterial infectious diseases.

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Targeting virulence not viability in the search for future antibacterials

Abstract: New antibacterials need new approaches to overcome the problem of rapid antibiotic resistance. Here we review the development of potential new antibacterial drugs that do not kill bacteria or inhibit their growth, but combat disease instead by targeting bacterial virulence.

Cited by 152 publications

References 77 publications

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

Structure of the Acinetobacter baumannii Dithiol Oxidase DsbA Bound to Elongation Factor EF-Tu Reveals a Novel Protein Interaction Site

Targeted treatment for bacterial infections: prospects for pathogen-specific antibiotics coupled with rapid diagnostics

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