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Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs.

ABSTRACT: Multiple drug resistance is the main obstacle in the treatment of bacterial diseases. Resistance against antibiotics demands the exploration of new antimicrobial drug targets. A variety of in silico and genetic approaches show that the enzymes of the riboflavin biosynthetic pathway are crucial for the survival of bacteria. This pathway is absent in humans thus enzymes of the riboflavin biosynthetic pathway are emerging drug targets for resistant pathogenic bacterial strains. Exploring the structural details, their mechanism of action, intermediate elucidation, and interaction analysis would help in designing suitable inhibitors of these enzymes. The riboflavin biosynthetic pathway consists of seven distinct enzymes, namely, 3,4-dihydroxy-2-butanone 4-phosphate synthase, GTP cyclohydrolase II, pyrimidine deaminase/reductase, phosphatase, lumazine synthase, and riboflavin synthase. The present review summarizes the research work that has been carried out on these enzymes in terms of their structures, active site architectures, and molecular mechanism of catalysis. This review also walks through small molecule inhibitors that have been developed against several of these enzymes.

SUBMITTER: Islam Z

PROVIDER: S-EPMC10366380 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs.

Islam Zeyaul Z Kumar Pankaj P

Frontiers in molecular biosciences 20230711

Multiple drug resistance is the main obstacle in the treatment of bacterial diseases. Resistance against antibiotics demands the exploration of new antimicrobial drug targets. A variety of <i>in silico</i> and genetic approaches show that the enzymes of the riboflavin biosynthetic pathway are crucial for the survival of bacteria. This pathway is absent in humans thus enzymes of the riboflavin biosynthetic pathway are emerging drug targets for resistant pathogenic bacterial strains. Exploring the ...[more]

PMID: 37496776

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Project description:In recent decades, there has been an increase in the occurrence of fungal infections; yet, the arsenal of drugs available to fight invasive infections remains very limited. The development of new antifungal agents is hindered by the restricted number of molecular targets that can be exploited, given the shared eukaryotic nature of fungi and their hosts which often leads to host toxicity. In this paper, we examine the riboflavin biosynthetic pathway as a potential novel drug target. Riboflavin is an essential nutrient for all living organisms. Its biosynthetic pathway does not exist in humans, who obtain riboflavin through their diet. Our findings demonstrate that all enzymes in the pathway are essential for Candida albicans, Candida glabrata, and Saccharomyces cerevisiae. Auxotrophic strains, which mimic a drug targeting the biosynthesis pathway, experience rapid mortality in the absence of supplemented riboflavin. Furthermore, RIB1 is essential for virulence in both C. albicans and C. glabrata in a systemic mouse model. The fungal burden of a RIB1 deletion strain is significantly reduced in the kidneys and brain of infected mice, and this reduction becomes more pronounced over time. Nevertheless, auxotrophic cells can still take up external riboflavin when supplemented. We identified Orf19.4337 as the riboflavin importer in C. albicans and named it Rut1. We found that Rut1 only facilitates growth at external riboflavin concentrations that exceed the physiological concentrations in the human body. This suggests that riboflavin uptake is unlikely to serve as a resistance mechanism against drugs targeting the biosynthesis pathway. Interestingly, the uptake system in S. cerevisiae is more effective than in C. albicans and C. glabrata, enabling an auxotrophic S. cerevisiae strain to outcompete an auxotrophic C. albicans strain in lower riboflavin concentrations.ImportanceCandida species are a common cause of invasive fungal infections. Candida albicans, in particular, poses a significant threat to immunocompromised individuals. This opportunistic pathogen typically lives as a commensal on mucosal surfaces of healthy individuals but it can also cause invasive infections associated with high morbidity and mortality. Currently, there are only three major classes of antifungal drugs available to treat these infections. In addition, the efficacy of these antifungal agents is restricted by host toxicity, suboptimal pharmacokinetics, a narrow spectrum of activity, intrinsic resistance of fungal species, such as Candida glabrata, to certain drugs, and the acquisition of resistance over time. Therefore, it is crucial to identify new antifungal drug targets with novel modes of action to add to the limited armamentarium.

Project description:Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and extra terminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by propidium iodide staining and flow cytometry, resulting in increased and decreased proportions of NET cells in G1, and S and G2 phases, respectively. RNA Sequencing analysis revealed that these JQ1 effects were associated with increased histone 2B expression, and likely mediated through altered activity of bromodomain-containing (Brd) proteins. Assessment of JQ1 in vivo, using a pancreatic beta cell-specific conditional Men1 knockout mouse model that develops PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, P<0.0005), assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, P<0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors may provide new treatments for NETs.

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Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs.

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Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs.

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