The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors

Rohde, Kyle H.; Sorci, Leonardo

doi:10.3389/fmicb.2020.634640

Cited by 9 publications

(11 citation statements)

References 86 publications

(99 reference statements)

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“…As previously observed using a variety of INH concentrations [47], 1 µg/ ml INH significantly reduced the levels of nicotinamide adenine dinucleotide (NAD + ) (Figure 4B and Table 1). Other workers also found that 6.4 µg/ml INH alters levels of many metabolites [46].…”

Section: Resultssupporting

confidence: 80%

Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages

Rijal,

Gomer

2024

Preprint

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Mycobacterium tuberculosis(Mtb), the bacterium that causes tuberculosis (TB), can be difficult to treat because of drug resistance. Increased intracellular polyphosphate (polyP) inMtbenhances resistance to antibiotics, and capsular polyP inNeisseria gonorrhoeaepotentiates resistance to antimicrobials. The mechanism by which bacteria utilize polyP to adapt to antimicrobial pressure is not known. In this study, we found thatMtbadapts to the TB frontline antibiotic isoniazid (INH) by enhancing the accumulation of cellular, extracellular, and cell surface polyP. Gallein, a broad-spectrum inhibitor of the polyphosphate kinase that synthesizes polyP, prevents this INH-induced increase in extracellular and cell surface polyP levels. Gallein and INH work synergistically to attenuateMtb’s ability to grow inin vitroculture and within human macrophages.Mtbwhen exposed to INH, and in the presence of INH, gallein inhibits cell envelope formation in most but not allMtbcells. Metabolomics indicated that INH or gallein have a modest impact on levels ofMtbmetabolites, but when used in combination, they significantly reduce levels of metabolites involved in cell envelope synthesis and amino acid, carbohydrate, and nucleoside metabolism, revealing a synergistic effect. These data suggest that gallein represents a promising avenue to potentiate the treatment of TB.Author summaryMycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB), which is responsible for more deaths than any other infectious disease. The alarming prevalence of drug-resistantMtbstrains has further exacerbated this global health crisis. Some pathogenic bacteria such asMtbappear to increase levels of polyphosphate as a defense against antibiotics. We found that gallein, a small molecule inhibitor of bacterial polyphosphate kinases, strongly potentiates the ability of the frontline anti-tuberculosis drug isoniazid to inhibit the growth ofMtbboth alone and in human macrophages. This has unveiled vulnerabilities inMtbthat could be strategically leveraged to reverse INH resistance.

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Section: Resultssupporting

confidence: 80%

Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages

Rijal,

Gomer

2024

Preprint

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“…Additionally upregulated in the gshT mutant strain was the nicotinamidase gene pncA . PncA is a functionally confirmed nicotinamidase in GAS ( 36 ) and plays an important role in the NAD + salvage and recycling pathway ( 37 ). Since GAS cannot de novo synthesize NAD + , it is dependent on salvage of the exogenous pyridine precursors, nicotinamide or nicotinic acid (vitamin B 3 ) ( 36 ).…”

Section: Resultsmentioning

confidence: 99%

Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion

Brouwer

Jespersen

Ong

et al. 2022

mBio

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“…SNP in nadD upstream region is associated with Pyrazinamide resistance. NadD is involved in NAD biosynthesis, which is targeted by Isoniazid, Pyrazinamide and some other promising antimycobacterial drugs [68].…”

Section: Discussionmentioning

confidence: 99%

Feature selection and aggregation for antibiotic resistance GWAS inMycobacterium tuberculosis: a comparative study

Reshetnikov

Bykova

Kuleshov

et al. 2022

Preprint

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Drug resistance (DR) remains a global healthcare concern. In contrast to other human bacterial pathogens, acquiring mutations in the genome is the main mechanism of drug resistance for Mycobacterium tuberculosis (MTB). For some antibiotics resistance of a particular isolate can be predicted with high confidence knowing whether specific mutations occurred, but for some antibiotics our knowledge of resistance mechanism is moderate. Statistical machine learning (ML) methods are used in attempts to infer new genes implicated in drug resistance. These methods use large collections of isolates with known whole-genome sequences and resistance status for different drugs. However, high correlations between the presence or absence of resistance to drugs that are used together in one treatment regimen complicate inference of causal mutations by traditional ML. Recently, several new methods were suggested to deal with the problem of correlations of response variables in training data. In this study, we applied the following methods to tackle the confounding effect of resistance co-occurrence in a dataset of approximately 13 000 complete genomes of MTB with characterized resistance status for 13 drugs: logistic regression with different regularization penalty functions, a polynomial-time algorithm for best-subset selection problem (ABESS), and "Hungry, Hungry SNPos" (HHS) method. We compared these methods by the ability to select known causal mutations for the resistance to each particular drug and not to select mutations in genes that are known to be associated with resistance to other drugs. ABESS significantly outperformed the others selecting more relevant sets of mutations. We also showed that aggregation of rare mutations into features indicating changes of PFAM domains increased the quality of prediction and these features were majorly selected by ABESS.

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The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors

Cited by 9 publications

References 86 publications

Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages

Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages

Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion

Feature selection and aggregation for antibiotic resistance GWAS inMycobacterium tuberculosis: a comparative study

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