The degradation of phenylacetate (PA) was investigated as a model to explore aromatic compound breakdown in the fungal system. Fungal strains capable of utilizing PA as their sole carbon source were isolated using a minimal solid medium supplemented with 0.5 % PA. Subsequent cultivation in minimum liquid medium revealed that selected fungal strains, including Trametes versicolor TV0876 and TV3295, Paecilomyces hepiali PH4477, and Akanthomyces muscarius AM1091, efficiently removed PA within 24 h. HPLC analysis of culture supernatants from various fungal strains revealed a time-dependent accumulation of 2-hydroxyphenylacetate (2-HPA) and 4-hydroxyphenylacetate (4-HPA), two key major metabolic products primarily found in ascomycetes and basidiomycetes, respectively. This suggests that the first hydroxylation of PA is catalyzed by two distinct hydroxylases, one for each fungal group. Furthermore, fungal species that make 4-HPA also produce phenylethanol (PE), indicating a distinct catabolic mechanism to remove PA by direct reduction of PA to PE. A. muscarius AM1091, identified as the most efficient PA degrader in this study, was studied further to determine the biochemical pathway of PA degradation. RNA-Seq and RT-PCR analyses of AM1091 revealed two oxidative enzyme genes, CYP1 and DIO4, upregulated in the presence of PA. Targeted disruption utilizing preassembled Cas9-gRNA ribonucleoprotein complexes and homologous DNAs harboring the URA3 gene as an auxotrophic marker resulted in the cyp1 and dio4 mutant strains. The cyp1 mutant was incapable of converting PA to 2-HPA, indicating its involvement in the C2 hydroxylation, whereas the dio4 mutant was unable to degrade 2,5-dihydroxyphenylacetate (2,5-DHPA), resulting in the accumulation of 2,5-DHPA. Our findings indicate that A. muscarius AM1091 degrades PA through the activities of CYP1 and DIO4 for the C2 hydroxylation and subsequent ring-opening reactions, respectively.

13 Jun 2024·Journal of Medicinal Chemistry

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents

Article

Author: Wei, Yu-Jia ; Zhang, Shao-Lin ; Zhang, Jing ; Li, Shu-Rui ; Tan, Yi-Min ; Zhou, Cheng-He ; Hu, Yue-Gao

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.

01 Nov 2023·Applied Biochemistry and Biotechnology

Computational Modelling, Functional Characterization and Molecular Docking to Lead Compounds of Bordetella pertussis Diaminopimelate Epimerase

Article

Author: Praveen, Afsana ; Khanna, Suruchi M ; Singh, Shilpy

Bordetella pertussis, the causative agent of whooping cough, is an opportunistic virulent bacterial pathogen that is resistant to a wide range of antibiotics due to a variety of resistance mechanisms. Looking at the increasing number of infections caused by B. pertussis and its resistance to diverse antibiotics, it is essential to develop alternative strategies to fight against B. pertussis. Diaminopimelate epimerase (DapF) is an important enzyme of the lysine biosynthesis pathway in B. pertussis that catalyzes the formation of meso-2, 6-diaminoheptanedioate (meso-DAP), which is an important step in lysine metabolism. Therefore, Bordetella pertussis diaminopimelate epimerase (DapF) becomes an ideal target for antimicrobial drug development. In the present study, computational modelling, functional characterization, binding studies, and docking studies of BpDapF with lead compounds were carried out using different in silico tools. In silico prediction results in the secondary structure, 3-D structure analysis, and protein-protein interaction analysis of BpDapF. Docking studies further showed the respective amino acid residues for ligands in the phosphate‑binding loop of BpDapF play a vital role in the formation of H‑bonds with these ligands. The site where the ligand was bound is a deep groove, which is regarded as the binding cavity of the protein. Biochemical studies indicated that Limonin (binding energy - 8.8 kcal/mol), Ajmalicine (binding energy - 8.7 kcal/mol), Clinafloxacin (binding energy - 8.3 kcal/mol), Dexamethasone (binding energy - 8.2 kcal/mol), and Tetracycline (binding energy - 8.1 kcal/mol) exhibited promising binding towards the drug target DapF of B. pertussis in comparison with the binding between other drugs and act as the potential inhibitors of BpDapF that eventually can reduce the catalytic activity of BpDapF.

100 Deals associated with Clinafloxacin

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-	Clinafloxacin	-	DB14025

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Discovery	-	Pfizer Inc.	-
Bacterial Infections	Discovery	JP	-	-
Bacterial Infections	Discovery	US	-	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Pubmed \| Clin Infect Dis	Not Applicable	Febrile Neutropenia	541	Clinafloxacin	dbrguwpals(rkbodcqhbl) = umxuyrpmij johxfwzkkr (ziritnhele ) View more	-	01 Feb 2001
				Imipenem	dbrguwpals(rkbodcqhbl) = wjbggctfal johxfwzkkr (ziritnhele ) View more

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