A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes
| Autor: | Paul F. Agris, Sheetal Ramachandran, Thorsten M. Seyler, Haein Kim, Christina Moore |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) In silico 030106 microbiology novel anti-infective tRNA MRSA medicine.disease_cause Biochemistry Microbiology biofilm tRNA-dependent gene regulation 03 medical and health sciences Transcription (biology) medicine RNA target Pharmacology (medical) General Pharmacology Toxicology and Pharmaceutics Gene biology Communication lcsh:RM1-950 Biofilm RNA biology.organism_classification 030104 developmental biology Infectious Diseases lcsh:Therapeutics. Pharmacology Staphylococcus aureus Bacteria Function (biology) |
| Zdroj: | Antibiotics Antibiotics, Vol 10, Iss 41, p 41 (2021) |
| ISSN: | 2079-6382 |
| Popis: | Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains. |
| Databáze: | OpenAIRE |
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