Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Frohlich, Kyla M.; Weintraub, Spencer F.; Bell, Janeen T.; Todd, Gabrielle C.; Väre, Ville Y. P.; Schneider, Ryan; Kloos, Zachary A.; Tabe, Ebot S.; Cantara, William A.; Stark, Caren J.; Onwuanaibe, Urenna J.; Duffy, Bryan C.; Basanta‐Sanchez, Maria; Kitchen, Douglas B.; McDonough, Kathleen A.; Agris, Paul F.

doi:10.1002/cmdc.201800744

Cited by 19 publications

(31 citation statements)

References 92 publications

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“…Numerous imidazoles are readily found as an efficient antibacterial against both gram‐positive and gram‐negative pathogens such as Escherichia coli , Bacillus proteus , Staphylococcus aureus , Bacillus subtili , Pseudomonas aeruginosa , and Helicobacter pyloriurease , etc. Imidazole derivatives have been not only targeted as antibacterial but also targeted successfully a wide range of bacterial sources such as β‐ketoacyl‐acyl carrier protein synthase III (FabH), β‐Lactamases, glutamate racemase, DNA gyrase and topoisomerase and urease …”

Section: Discussionmentioning

confidence: 99%

Synthesis and discovery of N‐(1‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[1,1′‐biphenyl]‐2‐carboxamide derivatives as antimicrobial agents

Ashok

Shivananda

Prakash

et al. 2020

Journal of Heterocyclic Chem

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Novel dihydro‐1H‐imidazole‐2‐yl)‐[1,1′‐biphenyl]‐2‐carboxamides (4a‐l) was achieved using a three‐step synthesis process and evaluated as antimicrobial agents. These compounds were characterized through FTIR, NMR, LCMS and evaluated for DNA gyrase inhibition potentials and antimicrobial properties against Gram‐negative bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), Klebsiella pneumoniae MTCC 530 and Gram‐positive bacteria Staphylococcus aureus (MTCC 3160), Corynebacterium diphtheriae (MTCC 116) and Streptococcus pyogenes (MTCC 442). Excellent DNA gyrase inhibition exhibited by compound 4f (IC50 0.2 μM and relative percentage activity 96.24%). A broad spectrum of antimicrobial activity showed by compounds 4d, 4f and 4 k with a Minimal Inhibitory Constant (MIC) of 1.05, 1.35 and 1.25 μg mL−1, respectively.

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Section: Discussionmentioning

confidence: 99%

Synthesis and discovery of N‐(1‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[1,1′‐biphenyl]‐2‐carboxamide derivatives as antimicrobial agents

Ashok

Shivananda

Prakash

et al. 2020

Journal of Heterocyclic Chem

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“…isolates of methicillin-resistant Staphylococcus aureus (MRSA) (34). While PKZ18 provides an important proof of principle showing that small molecule antibiotics are suitable for targeting the T-box mechanism, further development is required.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Hines and colleagues showed that the anti-terminator "T-box" can be targeted with substituted oxazolidinones (13,(34)(35)(36)(37)(38)(39). We previously demonstrated that PKZ18 selectively targets Stem I Specifier Loops in Gram-positive bacteria and directly reduces Tbox transcriptional read-through of the associated genes.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria

Väre

Schneider

Kim

et al. 2020

Antimicrob Agents Chemother

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Bacterial infections and the rise of antibiotic resistance, especially multidrug resistance, have generated a clear need for discovery of novel therapeutics. We demonstrated that a small molecule drug PKZ18 targets the T-box mechanism and inhibits bacterial growth. The T-box is a structurally conserved riboswitch-like gene regulator in the 5′-untranslated region of numerous essential genes of Gram-positive bacteria. T-boxes are stabilized by cognate, unacylated tRNA ligands, allowing the formation of an anti-terminator hairpin in the mRNA that enables transcription of the gene. In the absence of an unacylated cognate tRNA, transcription is halted due to the formation of a thermodynamically more stable terminator hairpin. PKZ18 targets the site of the codon/anticodon interaction of the conserved Stem I and reduces T-box controlled gene expression. Here we show that novel analogs of PKZ18 have improved minimum inhibitory concentrations, bactericidal effects against methicillin resistant Staphylococcus aureus (MRSA), and increased efficacy in nutrient limiting conditions. The analogs have reduced cytotoxicity against eukaryotic cells compared to PKZ18. The PKZ18 analogs acted synergistically with aminoglycosides to significantly enhance the efficacy of the analogs and aminoglycosides, further increasing their therapeutic windows. RNA sequencing showed that the analog PKZ18-22 affects expression of 8 of 12 T-box controlled genes in a statistically significant manner, but not other 5′UTR regulated genes in MRSA. Very low levels of resistance further support the existence of multiple T-box targets for PKZ18 analogs in the cell. Together the multiple targets, low resistance, and synergy make PKZ18 analogs promising drugs for development and future clinical applications.

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“…Recently, a small‐molecule named PKZ18 was identified that showed inhibitory properties against multiple T‐box riboswitches and exhibited potent inhibitory activity against Gram‐positive but not Gram‐negative bacteria (Fig. ).…”

Section: T‐box Riboswitch As a Promising Drug Targetmentioning

confidence: 99%

An evolving tale of two interacting RNAs—themes and variations of the T‐box riboswitch mechanism

Suddala

Zhang

2019

IUBMB Life

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T‐box riboswitches are a widespread class of structured noncoding RNAs in Gram‐positive bacteria that regulate the expression of amino acid‐related genes. They form negative feedback loops to maintain steady supplies of aminoacyl‐transfer RNAs (tRNAs) to the translating ribosomes. T‐box riboswitches are located in the 5′ leader regions of mRNAs that they regulate and directly bind to their cognate tRNA ligands. T‐boxes further sense the aminoacylation state of the bound tRNAs and, based on this readout, regulate gene expression at the level of transcription or translation. T‐box riboswitches consist of two conserved domains—a 5′ Stem I domain that is involved in specific tRNA recognition and a 3′ antiterminator/antisequestrator (or discriminator) domain that senses the amino acid on the 3′ end of the bound tRNA. Interaction of the 3′ end of an uncharged but not charged tRNA with a thermodynamically weak discriminator domain stabilizes it to promote transcription readthrough or translation initiation. Recent biochemical, biophysical, and structural studies have provided high‐resolution insights into the mechanism of tRNA recognition by Stem I, several structural models of full‐length T‐box‐tRNA complexes, mechanism of amino acid sensing by the antiterminator domain, as well as kinetic details of tRNA binding to the T‐box riboswitches. In addition, translation‐regulating T‐box riboswitches have been recently characterized, which presented key differences from the canonical transcriptional T‐boxes. Here, we review the recent developments in understanding the T‐box riboswitch mechanism that have employed various complementary approaches. Further, the regulation of multiple essential genes by T‐boxes makes them very attractive drug targets to combat drug resistance. The recent progress in understanding the biochemical, structural, and dynamic aspects of the T‐box riboswitch mechanism will enable more precise and effective targeting with small molecules. © 2019 IUBMB Life, 2019 © 2019 IUBMB Life, 71(8):1167–1180, 2019

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Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Cited by 19 publications

References 92 publications

Synthesis and discovery of N‐(1‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[1,1′‐biphenyl]‐2‐carboxamide derivatives as antimicrobial agents

Synthesis and discovery of N‐(1‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[1,1′‐biphenyl]‐2‐carboxamide derivatives as antimicrobial agents

Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria

An evolving tale of two interacting RNAs—themes and variations of the T‐box riboswitch mechanism

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