Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Yokokawa, Fumiaki

doi:10.5059/yukigoseikyokaishi.72.1239

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…This may provide the best of both words 256 ; whole cell activity to avoid compounds that fail to accumulate in live bacteria, plus defined mechanisms to reduce the effort wasted on nonspecific toxins and for efficient optimisation of any hits. Furthermore, much of this can now be done at very high throughput 255,257 , potentially offering both quality and quantity (see upper right quadrant of Figure 3a).…”

Section: Commented [Pk6]mentioning

confidence: 99%

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Scannell

Bosley²,

Hickman³

et al. 2022

Nat Rev Drug Discov

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Successful drug discovery is like finding oases of safety and efficacy in chemical and biological deserts. Screens in disease models, and other decision tools used in drug research and development (R&D), point towards oases when they score therapeutic candidates in a way that correlates with clinical utility in humans. Otherwise, they probably lead in the wrong direction. This line of thought can be quantified by using decision theory, in which 'predictive validity' is the correlation coefficient between the output of a decision tool and clinical utility across therapeutic candidates. Analyses based on this approach reveal that the detectability of good candidates is extremely sensitive to predictive validity, because the deserts are big and oases small. Both history and decision theory suggest that predictive validity is under-managed in drug R&D, not least because it is so hard to measure before projects succeed or fail later in the process. This article explains the influence of predictive validity on R&D productivity and discusses methods to evaluate and improve it, with the aim of supporting the application of more effective decision tools and catalysing investment in their creation.

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Section: Commented [Pk6]mentioning

confidence: 99%

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Scannell

Bosley²,

Hickman³

et al. 2022

Nat Rev Drug Discov

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“…The case of anti-tuberculosis drug discovery is a good example of this change in strategy: researchers moved away from target-based ADPs and returned to cell-based screening [85], with greater success in the discovery of novel, more diverse, lead molecules for subsequent optimization [86]. In general, cell-based screening results in higher variability and more complex data than the binary hit/no-hit of target-based screening, which is more difficult to relate with biologic phenomena.…”

Section: Reverse Genomics: Revival Of Cell-based Screeningmentioning

confidence: 99%

Antibiotic Discovery: Where Have We Come from, Where Do We Go?

2019

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Given the increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures—platforms—that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines. During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

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“…[140] By contrast, a return to whole-cell screening has enabled the identification of structurally diverse novel antitubercular hits. [141] Natural product isolation has yielded diverse hits with promising activity. These include two new marine diterpenoids 16a,b, belonging to the unusual isoneoamphilectane-class, isolated from the marine sponge Svenzea flava, along with semisynthetic derivative 16c and other known amphilectane diterpenes, which exhibited both strong growth inhibition of Mycobacterium tuberculosis H37Rv and low mammalian toxicity.…”

Section: Aureus Infection[135]mentioning

confidence: 99%

Natural Products as a Source for Novel Antibiotics

Moloney

2016

Trends in Pharmacological Sciences

248

163

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Natural products have historically been of crucial importance in the identification and development of antibacterial agents. Interest in these systems has waned in recent years, but the rapid emergence of resistant bacterial strains has forced their re-evaluation as a route to identify novel chemical skeletons with antibacterial activity for elaboration in drug development. This overview examines the current situation, highlights new natural product systems which have been found, together with re-examination of some old ones, and new technologies for their identification. While natural products certainly have the potential to re-emerge as a key start-point in antibacterial drug discovery, reports of new or reinvestigated structures need to be supported with sufficient quality chemical (solubility, stability), biochemical (including toxicity in particular, along with target information) and microbiological [minimum inhibitory concentration (MIC) and resistance frequency] validation data to assist in the identification of promising hit structures and to avoid wasted effort from trawling over already cultivated territory. This is particularly important in a resource-limited research environment.

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Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Cited by 7 publications

References 48 publications

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Predictive validity in drug discovery: what it is, why it matters and how to improve it

Antibiotic Discovery: Where Have We Come from, Where Do We Go?

Natural Products as a Source for Novel Antibiotics

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