Genetic Strategies for Identifying New Drug Targets

Trauner, Andrej; Sassetti, Christopher M.; Rubín, Eric J.

doi:10.1128/microbiolspec.mgm2-0030-2013

Cited by 6 publications

(2 citation statements)

References 131 publications

(129 reference statements)

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“…This, in due time, should lead to concepts such as drug-likeness approaches, so that the finding of novel bacterial targets and the drug development process could be expedited. It is also important to keep in mind the need to understand the biology of the bacterial species we are aiming, since biological and, especially, genetic approaches will be a significant aid in the drug discovery process (Trauner, Sassetti and Rubin 2014 ).…”

Section: Looking For Alternativesmentioning

confidence: 99%

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan

Balsa²,

Espinosa

2015

FEMS Microbiology Reviews

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Type II (proteic) toxin–antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the ‘real’ world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein–protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed.

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Section: Looking For Alternativesmentioning

confidence: 99%

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan

Balsa²,

Espinosa

2015

FEMS Microbiology Reviews

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“…The F 1 -F 0 ATP synthase itself, the target for Bedaquiline (96), is rather conserved in the different lineages. However, in MAF L5 and MTB L2 we detected potentially deleterious mutations in atp genes (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

Ofori-Anyinam

Riley

Jobarteh

et al. 2019

Preprint

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Pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an 3 adaptation to low oxygen tension 4 5 Summary: 27 The geographically restricted M. africanum lineages (MAF) are primarily found in West Africa, where 28 they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known 29 about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu 30 stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully 31 understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 32 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport 33 Chain and Central Carbon Metabolic pathway in an attempt to explain these metabolic differences. 34 Furthermore, we determined, in silico, whether each mutation could affect the function of genes 35 encoding enzymes in these pathways. 36 We found more potentially deleterious mutations in these pathways in MAF lineages compared to 37 MTB lineages. Additionally, we found that convergent evolution in these pathways occurred 38 between MAF and some MTB lineages. 39 Generally, our findings show further differences between MAF and MTB lineages that may have 40 contributed to the MAF clinical-and growth phenotype and may indicate potential adaptation of 41 MAF lineages to a distinct ecological niche, that we suggest may include areas characterized by low 42 oxygen tension. 43 44 Running title: The M. africanum respiratory chain and carbon metabolic pathway 45 46 Transport, Carbon Metabolism 48 49 50 51 3 1 Introduction 52 The Mycobacterium tuberculosis complex (MTBC) consists of a group of human-adapted ecotypes-53 Mycobacterium tuberculosis sensu stricto, Mycobacterium africanum, Mycobacterium canetti and 54 animal-adapted ecotypes (1-4). There are seven known MTBC lineages (L) associated with particular 55 geographic regions and adapted to specific human populations. These are the five lineages that 56 make up M. tuberculosis sensu stricto (lineages 1-4 and lineage 7) and the two M. africanum lineages 57 (lineages 5 and 6). Africa uniquely has a representation of all seven lineages. 58 MTBC strains from the seven lineages differ on average by about 1200 single nucleotide 59 polymorphisms (5), with clear distinction between MAF and MTB lineages (6-8). 60 MTB Lineages 2 and 4 are more widespread geographically, more pathogenic and more 61 transmissible, while MAF Lineages are exclusively found in West Africa and less transmissible (5, 9, 62 10). Clinically, MTB L4 is relatively more virulent than MAF L6 as evidenced by significantly faster 63 progression, in contacts of infectious cases, to active disease (11). MAF lineages are associated with 64 extrapulmonary disease and MAF L6 more commonly causes disease in immunocompromised 65 persons and those with lower Body Mass Index, implying a more opportunistic pathogen (10, 12). 66 Furthermore, MAF L5 a...

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Transcriptomics as a tool to discover new antibacterial targets

et al. 2017

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The emergence of antibiotic-resistant pathogens, multiple drug-resistance, and extremely drug-resistant strains demonstrates the need for improved strategies to discover new drug-based compounds. The development of transcriptomics, proteomics, and metabolomics has provided new tools for global studies of living organisms. However, the compendium of expression profiles produced by these methods has introduced new scientific challenges into antimicrobial research. In this review, we discuss the practical value of transcriptomic techniques as well as their difficulties and pitfalls. We advocate the construction of new databases of transcriptomic data, using standardized formats in addition to standardized models of bacterial and yeast similar to those used in systems biology. The inclusion of proteomic and metabolomic data is also essential, as the resulting networks can provide a landscape to rationally predict and exploit new drug targets and to understand drug synergies.

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Genetic Strategies for Identifying New Drug Targets

Cited by 6 publications

References 131 publications

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

Transcriptomics as a tool to discover new antibacterial targets

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