Considerations and caveats in anti-virulence drug development

Maura, Damien; Ballok, Alicia E.; Rahme, Laurence G.

doi:10.1016/j.mib.2016.06.001

Cited by 128 publications

(115 citation statements)

References 65 publications

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“…Although S. aureus is a common member of the normal human microflora, it is also a frequent cause of infection in both healthy and immunocompromised individuals. Identification of the pathways by which S. aureus responds to human cues may aid in the development of novel therapeutics that block sensing of the host environment and thereby reduce pathogen virulence (30).…”

Section: Discussionmentioning

confidence: 99%

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Lopez¹,

Tan²,

Yan³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The type VII secretion system (T7SS) of Staphylococcus aureus is a multiprotein complex dedicated to the export of several virulence factors during host infection. This virulence pathway plays a key role in promoting bacterial survival and the long-term persistence of staphylococcal abscess communities. The expression of the T7SS is activated by bacterial interaction with host tissues including blood serum, nasal secretions, and pulmonary surfactant. In this work we identify the major stimulatory factors as host-specific cisunsaturated fatty acids. Increased T7SS expression requires host fatty acid incorporation into bacterial biosynthetic pathways by the S. aureus fatty acid kinase (FAK) complex, and FakA is required for virulence. The incorporated cis-unsaturated fatty acids decrease S. aureus membrane fluidity, and these altered membrane dynamics are partially responsible for T7SS activation. These data define a molecular mechanism by which S. aureus cells sense the host environment and implement appropriate virulence pathways.type VII secretion | Staphylococcus aureus | fatty acids | virulence

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Section: Discussionmentioning

confidence: 99%

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Lopez¹,

Tan²,

Yan³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The discovery phase of antivirulence therapies is characterized by the difficult choice of the most relevant preclinical assays to define success in the absence of bacterial death 8,72 . As surrogate outcomes may have little evidence of relevance for clinical outcome, the risk of failure in clinical trials is high.…”

Section: Compassionate Usementioning

confidence: 99%

The global preclinical antibacterial pipeline

Theuretzbacher¹,

et al. 2019

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| Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of nontraditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work , focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

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“…Identifying genes that are essential under various conditions that mimic host infection may provide additional genes that could serve as high value targets for the antibiotic development. Notably, these approaches may also identify non-traditional targets, such as bacterial virulence factors, which have recently been proposed as targets for the development of antimicrobials with novel mechanisms of action [57,58]. …”

Section: Essential Genes As Targets For Antibiotic Discoverymentioning

confidence: 99%

Using bacterial genomes and essential genes for the development of new antibiotics

Fields

Lee

McConnell

2017

Biochemical Pharmacology

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The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20 years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics.

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Considerations and caveats in anti-virulence drug development

Cited by 128 publications

References 65 publications

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

The global preclinical antibacterial pipeline

Using bacterial genomes and essential genes for the development of new antibiotics

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