DNA gyrase inhibitors: Progress and synthesis of potent compounds as antibacterial agents

Khan, Tabassum; Sankhe, Kaksha; Suvarna, Vasanti; Sherje, Atul P.; Patel, Kavitkumar; Dravyakar, Bhushan R.

doi:10.1016/j.biopha.2018.04.021

Cited by 184 publications

(114 citation statements)

References 69 publications

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“…Fluoroquinolones (FQs) represent one of the most commonly used antibiotics to treat human and veterinary infections due to their excellent bioavailability, good tissue penetration, relatively low toxicity, and broad-spectrum activity [13][14][15] . Numerous FQ derivatives have been synthesized by modifying the chemical structure of the 1,8 naphthyridine core in order to increase their antibacterial efficiency and improve their pharmacokinetics [16][17][18][19][20] . These modifications have led to the synthesis of norfloxacin and ciprofloxacin, two antibiotics with increased activity against Gram-negative bacteria, which are still marketed 13 .…”

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confidence: 99%

The challenge of intracellular antibiotic accumulation, a function of fluoroquinolone influx versus bacterial efflux

et al. 2020

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With the spreading of antibiotic resistance, the translocation of antibiotics through bacterial envelopes is crucial for their antibacterial activity. In Gram-negative bacteria, the interplay between membrane permeability and drug efflux pumps must be investigated as a whole. Here, we quantified the intracellular accumulation of a series of fluoroquinolones in population and in individual cells of Escherichia coli according to the expression of the AcrB efflux transporter. Computational results supported the accumulation levels measured experimentally and highlighted how fluoroquinolones side chains interact with specific residues of the distal pocket of the AcrB tight monomer during recognition and binding steps.

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The challenge of intracellular antibiotic accumulation, a function of fluoroquinolone influx versus bacterial efflux

et al. 2020

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“…The molecular mechanism indicated its intercalation with DNA as well as the formula of a topo II-stabilizing complex [38,39]. The success of anticancer and antibacterial drugs as DNA topoisomerases inhibitors [40] highlights the potential of topoisomerases from fungal cells as targets for the development of novel antifungals.…”

Section: Fungal Topoisomerases As Drug Targets For Acridine/acridone mentioning

confidence: 99%

‘Acridines’ as New Horizons in Antifungal Treatment

Gabriel

2020

Molecules

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Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic Candida species remain one of the leading causes of systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14α-demethylase and β-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.

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“…Indeed, DNA topology control is functional to an efficient processive synthesis, as well as the elimination of the stresses resulting from negative supercoiling and the concatenation of double-stranded DNA. The type II topoisomerase, DNA gyrase, is built on two subunits, gyrase A and gyrase B, which together form the catalytically active heterotetrameric enzyme (i.e., GyrA 2 B 2 ) [70]. The role of the A subunit is the breakage and rejoining of the double DNA strand, while the B subunit possesses the ATPase activity, which provides energy for the DNA supercoiling.…”

Section: Dna Topology Control and Regulationmentioning

confidence: 99%

Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

et al. 2020

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Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.

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DNA gyrase inhibitors: Progress and synthesis of potent compounds as antibacterial agents

Cited by 184 publications

References 69 publications

The challenge of intracellular antibiotic accumulation, a function of fluoroquinolone influx versus bacterial efflux

The challenge of intracellular antibiotic accumulation, a function of fluoroquinolone influx versus bacterial efflux

‘Acridines’ as New Horizons in Antifungal Treatment

Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

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