Combatting antimicrobial resistance via the cysteine biosynthesis pathway in bacterial pathogens

Hicks, Joanna; Oldham, K.E.; McGarvie, Jack; Walker, Emma J

doi:10.1042/bsr20220368

Cited by 15 publications

(5 citation statements)

References 135 publications

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“…The synthesis of cysteine is a two-step process, catalyzed by two enzymes, serine acetyltransferase (CysE) catalyzes the rst step, producing O-acetylserine. O-acetylserine sulfhydrylase combines O-acetylserine with a sulfur source for the synthesis of cysteine [27]. The deletion of CysE in Salmonella typhimurium renders it incapable of synthesizing O-acetylserine, leading to less cysteine, and therefore, lesser glutathione production, increasing its susceptibility to oxidative stress [28].…”

Section: Discussionmentioning

confidence: 99%

Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis

Casaro,

Prim,

Gonzalez

et al. 2024

Preprint

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Background Metritis is a prevalent uterine disease that affects the welfare, fertility, and survival of dairy cows. The uterine microbiome from cows that develop metritis and those that remain healthy do not differ from calving until 2 days postpartum, after which there is a dysbiosis of the uterine microbiome characterized by a shift towards opportunistic pathogens such as Fusobacteriota and Bacteroidota. Whether these opportunistic pathogens proliferate and overtake the uterine commensals could be determined by the type of substrates present in the uterus. The objective of this study was to integrate uterine microbiome and metabolome data to advance the understanding of the uterine environment in dairy cows that develop metritis. Holstein cows (n = 104) had uterine fluid collected at calving and at the day of metritis diagnosis. Cows with metritis (n = 52) were paired with cows without metritis (n = 52) based on days after calving. First, the uterine microbiome and metabolome were evaluated individually, and then integrated using network analyses. Results The uterine microbiome did not differ at calving but differed on the day of metritis diagnosis between cows with and without metritis. The uterine metabolome differed both at calving and on the day of metritis diagnosis between cows that did and did not develop metritis. Omics integration was performed between 6 significant bacteria genera and 153 significant metabolites on the day of metritis diagnosis. Integration was not performed at calving because there were no significant differences in the uterine microbiome. A total of 3 bacteria genera (i.e. Fusobacterium, Porphyromonas, and Bacteroides) were strongly correlated with 49 metabolites on the day of metritis diagnosis. Seven of the significant metabolites at calving were among the 49 metabolites strongly correlated with opportunistic pathogenic bacteria on the day of metritis diagnosis. The main metabolites have been associated with attenuation of biofilm formation by commensal bacteria, opportunistic pathogenic bacteria overgrowth, tissue damage and inflammation, immune evasion, and immune dysregulation. Conclusions The data integration presented herein helps advance the understanding of the uterine environment in dairy cows with metritis. The identified metabolites may provide a competitive advantage to the main uterine pathogens Fusobacterium, Porphyromonas and Bacteroides, and may be promising targets for future interventions aiming to reduce opportunistic pathogenic bacteria growth in the uterus.

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Section: Discussionmentioning

confidence: 99%

Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis

Casaro,

Prim,

Gonzalez

et al. 2024

Preprint

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“…Antimicrobial adjuvants that enhance the activity of drugs and can minimize microbial resistance has attracted much attention as an approach to strengthen the efficacy of existing drugs for the treatment of those ESKAPE bacteria ( Wright, 2016 ; Domalaon et al, 2018 ; Dubey et al, 2020 ). Although CysE inhibitors have been considered to become potential antimicrobial adjuvants ( Hicks et al, 2022 ), no reports are yet available showing CysE inhibitors could sensitize antibiotic responses to Gram-negative bacteria. As shown in this study, OGA could intensify the susceptibilities of the ESKAPE bacteria, including E. coli and K. pneumoniae , to carbapenems such as doripenem, meropenem, and imipenem, suggesting that CysE inhibitors may show promise as novel adjuvants to enhance antibiotic activity of carbapenems.…”

Section: Discussionmentioning

confidence: 99%

Alkyl gallates inhibit serine O-acetyltransferase in bacteria and enhance susceptibility of drug-resistant Gram-negative bacteria to antibiotics

Toyomoto,

Ono,

Shiba

et al. 2023

Front. Microbiol.

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A principal concept in developing antibacterial agents with selective toxicity is blocking metabolic pathways that are critical for bacterial growth but that mammalian cells lack. Serine O-acetyltransferase (CysE) is an enzyme in many bacteria that catalyzes the first step in l-cysteine biosynthesis by transferring an acetyl group from acetyl coenzyme A (acetyl-CoA) to l-serine to form O-acetylserine. Because mammalian cells lack this l-cysteine biosynthesis pathway, developing an inhibitor of CysE has been thought to be a way to establish a new class of antibacterial agents. Here, we demonstrated that alkyl gallates such as octyl gallate (OGA) could act as potent CysE inhibitors in vitro and in bacteria. Mass spectrometry analyses indicated that OGA treatment markedly reduced intrabacterial levels of l-cysteine and its metabolites including glutathione and glutathione persulfide in Escherichia coli to a level similar to that found in E. coli lacking the cysE gene. Consistent with the reduction of those antioxidant molecules in bacteria, E. coli became vulnerable to hydrogen peroxide-mediated bacterial killing in the presence of OGA. More important, OGA treatment intensified susceptibilities of metallo-β-lactamase-expressing Gram-negative bacteria (E. coli and Klebsiella pneumoniae) to carbapenem. Structural analyses showed that alkyl gallate bound to the binding site for acetyl-CoA that limits access of acetyl-CoA to the active site. Our data thus suggest that CysE inhibitors may be used to treat infectious diseases caused by drug-resistant Gram-negative bacteria not only via direct antibacterial activity but also by enhancing therapeutic potentials of existing antibiotics.

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“…The cysteine biosynthetic pathway is a non-essential target that has been reported to be productive in antibacterial therapy [7]. Biotin, coenzyme A, Fe−S clusters, glutathione, methionine, and penicillin are some of the sulfur-containing biomolecules with cysteine as their precursor [8].…”

Section: Introductionmentioning

confidence: 99%

“…This, in turn, results in conventional antibiotics (e.g., Triazole) becoming effective at lower doses [10]. This highlights the possibility that treatment efficacy can be enhanced using cysteine biosynthesis inhibitors by reducing the antibiotic dosage, consequently decreasing resistance and its spread [7]. These factors suggest that the chemical inhibition of OASS isoforms could be a promising strategy for the development of antibiotic adjuvants [4].…”

Section: Introductionmentioning

confidence: 99%

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

Elebiju,

Oduselu,

Ogunnupebi

et al. 2024

Pharmaceuticals

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The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

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Combatting antimicrobial resistance via the cysteine biosynthesis pathway in bacterial pathogens

Cited by 15 publications

References 135 publications

Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis

Integrating uterine microbiome and metabolome to advance the understanding of the uterine environment in dairy cows with metritis

Alkyl gallates inhibit serine O-acetyltransferase in bacteria and enhance susceptibility of drug-resistant Gram-negative bacteria to antibiotics

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

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