Proteomic Profile of
            <i>Mycobacterium Tuberculosis</i>
            after Eupomatenoid-5 Induction Reveals Potential Drug Targets

Ghiraldi-Lopes, Luciana Dias; Campanerut-Sá, Paula Az; Meneguello, Jean Eduardo; Seixas, Flávio Augusto Vicente; Lopes-Ortiz, Mariana Aparecida; Scodro, Regiane Bertin de Lima; Pires, Claudia T. A.; Silva, Rosi Z da; Siqueira, Vera Ld; Nakamura, Celso Vataru; Cardoso, Rosilene Fressatti

doi:10.2217/fmb-2017-0023

Cited by 7 publications

(6 citation statements)

References 74 publications

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“…mgf without summing the scans by the Mascot Distiller software (version 2.3.2.0; Matrix Science, United Kingdom) and searched against the knowledgebase UniProtKB using the Mascot software (version 2.4.0; Matrix Science, United Kingdom). For the search, the following parameters were considered: taxonomy Salmonella and all entries (separately), monoisotopic mass, trypsin, allowing up to one missed cleavage site, peptide charge +2, +3 and +4, fixed modification for carbamidomethylation of cysteine residues and variable modification for oxidation of methionine residues, peptide and MS/MS tolerance equal to 0.1 Da [ 53 – 55 ], ESI-QUA-TOF for instrument. The proteins identifications by Mascot software were validated and the proteins were quantified by Scaffold software (version 4.7.2; Proteome Software, USA).…”

Section: Methodsmentioning

confidence: 99%

N-dodecanoyl-homoserine lactone influences the levels of thiol and proteins related to oxidation-reduction process in Salmonella

et al. 2018

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Quorum sensing is a cell-cell communication mechanism mediated by chemical signals that leads to differential gene expression in response to high population density. Salmonella is unable to synthesize the autoinducer-1 (AI-1), N-acyl homoserine lactone (AHL), but is able to recognize AHLs produced by other microorganisms through SdiA protein. This study aimed to evaluate the fatty acid and protein profiles of Salmonella enterica serovar Enteritidis PT4 578 throughout time of cultivation in the presence of AHL. The presence of N-dodecanoyl-homoserine lactone (C12-HSL) altered the fatty acid and protein profiles of Salmonella cultivated during 4, 6, 7, 12 and 36 h in anaerobic condition. The profiles of Salmonella Enteritidis at logarithmic phase of growth (4 h of cultivation), in the presence of C12-HSL, were similar to those of cells at late stationary phase (36 h). In addition, there was less variation in both protein and fatty acid profiles along growth, suggesting that this quorum sensing signal anticipated a stationary phase response. The presence of C12-HSL increased the abundance of thiol related proteins such as Tpx, Q7CR42, Q8ZP25, YfgD, AhpC, NfsB, YdhD and TrxA, as well as the levels of free cellular thiol after 6 h of cultivation, suggesting that these cells have greater potential to resist oxidative stress. Additionally, the LuxS protein which synthesizes the AI-2 signaling molecule was differentially abundant in the presence of C12-HSL. The NfsB protein had its abundance increased in the presence of C12-HSL at all evaluated times, which is a suggestion that the cells may be susceptible to the action of nitrofurans or that AHLs present some toxicity. Overall, the presence of C12-HSL altered important pathways related to oxidative stress and stationary phase response in Salmonella.

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Section: Methodsmentioning

confidence: 99%

N-dodecanoyl-homoserine lactone influences the levels of thiol and proteins related to oxidation-reduction process in Salmonella

et al. 2018

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“…[6] Transposonm utagenesis experiments have confirmed that KARI is an essential gene in Mt [7] and is also essential in asymptomatic Escherichia coli found in urine. [8] In addition, ap roteomic profile of Mt after eupomatenoid-5 induction revealed KARI as ad rug target, [9] and deletion mutation experiments in Fusarium graminearum demonstrated that KARI is essentialf or full virulence in this plant pathogen that causes head blight. [10] KARI is ab i-functional enzyme catalyzing an isomerization reactiona nd an NAD(P)H-mediated reduction.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Staphylococcus aureus Ketol‐Acid Reductoisomerase in Complex with Two Transition State Analogues that Have Biocidal Activity

Patel

Teran

Zheng

et al. 2017

Chemistry A European J

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Ketol-acid reductoisomerase (KARI) is an NAD(P)H and Mg -dependent enzyme of the branched-chain amino acid (BCAA) biosynthesis pathway. Here, the first crystal structures of Staphylococcus aureus (Sa) KARI in complex with two transition state analogues, cyclopropane-1,1-dicarboxylate (CPD) and N-isopropyloxalyl hydroxamate (IpOHA) are reported. These compounds bind competitively and in multi-dentate manner to KARI with K values of 2.73 μm and 7.9 nm, respectively; however, IpOHA binds slowly to the enzyme. Interestingly, intact IpOHA is present in only ≈25 % of binding sites, whereas its deoxygenated form is present in the remaining sites. This deoxy form of IpOHA binds rapidly to Sa KARI, but with much weaker affinity (K =21 μm). Thus, our data pinpoint the origin of the slow binding mechanism of IpOHA. Furthermore, we propose that CPD mimics the early stage of the catalytic reaction (preceding the reduction step), whereas IpOHA mimics the late stage (after the reduction took place). These structural insights will guide strategies to design potent and rapidly binding derivatives of these compounds for the development of novel biocides.

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“…More recently, KARI has also emerged as a promising drug target; [6,8,16,17] in both Mycobacterium tuberculosis ( Mt ) and uropathogenic Escherichia coli ( Ec ), KARI has been shown to be essential for growth and survival [16,17] . Consequently, diverse compounds that significantly inhibit KARI have recently been developed as potential anti‐microbial drug candidates [8,18–22] …”

Section: Introductionmentioning

confidence: 99%

Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

Bayaraa

Gaete

Sutiono

et al. 2022

Chemistry A European J

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There is an urgent global need for the development of novel therapeutics to combat the rise of various antibioticresistant superbugs. Enzymes of the branched-chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti-microbial drug development. Dihydroxy-acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an FeÀ S cluster for catalytic activity and has recently also gained attention as a catalyst in cell-free enzyme cascades. Two types of FeÀ S clusters have been identified in DHADs, i.e. [2FeÀ 2S] and [4FeÀ 4S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, Staphylococcus aureus and Campylobacter jejuni (SaDHAD and CjDHAD). Purified SaDHAD and CjDHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to ~19,000-fold increase with k cat as high as ~6.7 s À 1 ). Inductively-coupled plasma-optical emission spectroscopy (ICP-OES) measurements are consistent with the presence of [4FeÀ 4S] clusters in both enzymes. N-isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both SaDHAD (K i = 7.8 and 51.6 μM, respectively) and CjDHAD (K i = 32.9 and 35.1 μM, respectively). These compounds thus present suitable starting points for the development of novel anti-microbial chemotherapeutics.

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Proteomic Profile of Mycobacterium Tuberculosis after Eupomatenoid-5 Induction Reveals Potential Drug Targets

Abstract: Some of the differentially expressed proteins have the potential to be drug targets such as citrate synthase (Rv0896), phosphoglycerate kinase (Rv1437), ketol-acid reductoisomerase (Rv3001c) and ATP synthase alpha chain (Rv1308).

Cited by 7 publications

References 74 publications

N-dodecanoyl-homoserine lactone influences the levels of thiol and proteins related to oxidation-reduction process in Salmonella

N-dodecanoyl-homoserine lactone influences the levels of thiol and proteins related to oxidation-reduction process in Salmonella

Crystal Structures of Staphylococcus aureus Ketol‐Acid Reductoisomerase in Complex with Two Transition State Analogues that Have Biocidal Activity

Dihydroxy‐Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance

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