Abstract
Antibiotic resistance represents a significant threat worldwide. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known.
With the aim to speed up the drug discovery process and to reduce the limitations of target-based high-through put screenings (HTS) we envisioned N-((1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methyl)cyclohexanamine (pyrrole 1) through an alternative strategy based on the molecular hybridization of known drugs. Pyrrole 1 is a promising novel agent as it shows potent activity against various mycobacteria, including multi drug resistant (MDR) tuberculosis strains.
A subsequent structure-activity relationship (SAR) study revealed that the introduction of a phenyl ring on C5 of the pyrrole was a key element to switch the selectivity and the antimicrobial activity from mycobacteria to Gram+ve bacteria.
Based on these results, we designed and synthesized a new series of 1,5-diaryl-pyrrole derivatives active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram+ve and Gram-ve bacteria at concentrations similar than levofloxacin.
Microbiology studies revealed that the plausible target of this class of compounds is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
Lingua originale | English |
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Titolo della pubblicazione ospite | Abstract Book |
Pagine | 500-514 |
Numero di pagine | 1 |
Volume | 178 |
DOI | |
Stato di pubblicazione | Pubblicato - 2019 |
Evento | 3rd International StaPa Retreat - Roma Durata: 12 giu 2019 → 15 giu 2019 |
Convegno
Convegno | 3rd International StaPa Retreat |
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Città | Roma |
Periodo | 12/6/19 → 15/6/19 |
Keywords
- Antibacterial Agents
- Antimicrobial Resistance
- Bacterial Infections
- DNA gyrase
- Drug Resistance
- Drug design
- ESKAPE Bacteria
- Gram-negative bacteria
- Gram-positive bacteria
- Molecular Docking Simulation
- Molecular Structure
- Multi-drug resistance
- Pyrrole
- Structure-Activity Relationship