Halogenation of Biotin Protein Ligase Inhibitors Improves Whole Cell Activity against <i>Staphylococcus aureus</i>

Paparella, Ashleigh S.; Lee, Kwang J.; Hayes, Andrew; Feng, Jiage; Feng, Zikai; Cini, Danielle; Deshmukh, S. M.; Booker, Grant W.; Wilce, Matthew C. J.; Polyak, Steven W.; Abell, Andrew D.

doi:10.1021/acsinfecdis.7b00134

Cited by 28 publications

(68 citation statements)

References 41 publications

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“…No change in the antibacterial potency of BASA was observed when tested against a bioY knockout S. aureus strain (data not shown). Similarly, increasing the concentration of exogenous biotin in the growth media did not impede the internalization of a fluorescent BPL inhibitor containing the biotinyl group [30]. Together these observations suggest that BASA is imported into bacteria independently of BioY.…”

Section: Discussionmentioning

confidence: 73%

“…Purified apo protein was confirmed by native nano-electrospray ionization-mass spectrometry (nESI-MS) and by Western blot analysis as described previously [25,26]. An enzyme activity assay to measure the incorporation of biotin onto protein by BPL was performed as previously reported [30].…”

Section: Protein Methodsmentioning

confidence: 99%

“…Collectively, these data suggest that in vitro resistance to the BPL inhibitor is possible without significant associated fitness costs. To test if the resistance mechanisms identified were specific for BASA, all seven strains were subjected to antibacterial susceptibility assays against a panel of diverse antibiotics that included two known BPL inhibitors, namely biotinol-5 -AMP [32] and BPL223 (compound 4c in [30]). The evolved resistance mechanisms appeared specific to the BPL inhibitors as there was no change in susceptibility to β-lactams amoxicillin and methicillin (Table S1).…”

Section: Advanced Resistance Studies Identify Two Resistance Mechanismsmentioning

confidence: 99%

“…Several groups have reported on the development of anti-BPL compounds with antibacterial activity [15][16][17][18][19][30][31][32][33][34]. Bisubstrate analogs that occupy both the biotin and ATP-binding pockets and mimic the mode of binding adopted by biotinyl-5 -AMP have been particularly promising.…”

Section: Introductionmentioning

confidence: 99%

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Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

et al. 2020

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Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant Staphylococcus aureus (S. aureus). In S. aureus, BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro, as well as functioning as a transcription co-repressor. A low spontaneous resistance rate was measured for the compound (<10−9) and whole-genome sequencing of strains evolved during serial passaging in the presence of BASA identified two discrete resistance mechanisms. In the first, deletion of the biotin-dependent enzyme pyruvate carboxylase is proposed to prioritize the utilization of bioavailable biotin for the essential enzyme acetyl-CoA carboxylase. In the second, a D200E missense mutation in BPL reduced DNA binding in vitro and transcriptional repression in vivo. We propose that this second resistance mechanism promotes bioavailability of biotin by derepressing its synthesis and import, such that free biotin may outcompete the inhibitor for binding BPL. This study provides new insights into the molecular mechanisms governing antibacterial activity and resistance of BPL inhibitors in S. aureus.

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Section: Discussionmentioning

confidence: 73%

Section: Protein Methodsmentioning

confidence: 99%

Section: Advanced Resistance Studies Identify Two Resistance Mechanismsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

et al. 2020

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“…Today, a number of proteins are considered as promising drug targets for the development of antibiotics to treat staphylococcal infections. After extensive review of the literature for the last three years, the following proteins were considered as potential therapeutic drug targets for the development of antistaphylococcal agents: bacterial enoyl reductase (FabI) [3,4], transglycosylase (TGase) [5,6], sortase A [7][8][9][10][11][12][13], diapophytoene desaturase (CrtN) [14][15][16][17], type II topoisomerase [18][19][20][21], topoisomerase IV [22][23][24][25][26][27], filamentous temperature-sensitive protein Z (FtsZ) [28][29][30], UDP-N-acetylenolpyruvylglucosamine reductase (MurB) [31], lipoteichoic acid synthase (LtaS) [32], biotin protein ligase [33,34], peptide deformylase [35], Ser/Thr protein kinase STK1 [36], pentaerythritol tetranintrate reductase [37], peptide deformylase (PDF) [38,39], NorA efflux pump [40][41][42][43][44]…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

et al. 2019

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Aim. To identify novel putative drug targets of methicillin-resistant S. aureus (MRSA) through subtractive proteome analysis. Methods. Identification of non-homologous proteins in the human proteome, search of MRSA essential genes and evaluation of drug target novelty were performed using a protein BLAST server. Unique metabolic pathways identification was carried out using data and tools from KEGG (Kyoto Encyclopedia of Genes and Genomes). Prediction of sub-cellular proteins localization was performed using combination of PSORT v. 3.0.2, CELLO v. 2.5, iLoc-Gpos, and Pred-Lipo tools. Homology modeling was performed using SWISS-MODEL, Phyre2, I-TASSER web-servers and the MODELLER software. Results. Proteomes of six annotated methicillin-resistant strains : MRSA ATCC BAA-1680, H-EMRSA-15, LA MRSA ST398, MRSA 252, MRSA ST772, UTSW MRSA 55 were initially analyzed. The proteome analysis of the MRSA strains in several consequent steps allowed to identify two molecular targets: diadenylate cyclase and D-alanyl-lipoteichoic acid biosynthesis (DltB) protein which meet the requirements of being essential, membrane-bound, non-homologous to human proteome, involved in unique metabolic pathways and new in terms of not having approved drugs. Using the homology modeling approach, we have built three-dimensional structures of these proteins and predicted their ligand-binding sites. Conclusions. We used classical bioinformatics approaches to identify two molecular targets of MRSA :diadenylate cyclase and DltB which can be used for further rational drug design in order to find novel therapeutic agents for treatment of multidrug resistant staphylococcal infection. K e y w o r d s: molecular drug targets; methicillin-resistant Staphylococcus aureus; MRSA; subtractive proteome analysis.

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Halo‐1,2,3‐triazoles: Valuable Compounds to Access Biologically Relevant Molecules

Coelho,

Colas,

Ethève‐Quelquejeu

et al. 2024

ChemBioChem

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1,2,3‐triazole is an important building block in organic chemistry. It is also now well known as bioisostere for various functions, such as the amide or the ester bond, positioning it as key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4‐disubstituted 1,2,3‐triazole molecules but 1,4,5‐trisubstituted 1,2,3‐triazoles have emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction have been developed to access halo‐triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late‐stage modification of halo‐triazole derivatives by metal‐mediated cross‐coupling or halo‐exchange reactions offers the possibility to access highly functionalized molecules that can be used as a tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5‐trisubstituted halo‐1,2,3‐triazoles in biologically relevant molecules.

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Halogenation of Biotin Protein Ligase Inhibitors Improves Whole Cell Activity against Staphylococcus aureus

Cited by 28 publications

References 41 publications

Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

Halo‐1,2,3‐triazoles: Valuable Compounds to Access Biologically Relevant Molecules

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