To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 μM) than isoniazid (IC50 = 5.4 μM), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs.
The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes
the treatment of infectious diseases
in hospitals more difficult and increases the mortality of the patients.
In this study, we attempted to identify novel potent antibiotic candidate
compounds against S. aureus dihydrofolate reductase
(saDHFR). We performed three-step in silico structure-based
drug screening (SBDS) based on the crystal structure of saDHFR using
a 154,118 chemical compound library. We subsequently evaluated whether
candidate chemical compounds exhibited inhibitory effects on the growth
of the model bacterium: Staphylococcus epidermidis (S. epidermidis). The compound KB1 showed a strong
inhibitory effect on the growth of S. epidermidis. Moreover, we rescreened chemical structures similar to KB1 from
a 461,397 chemical compound library. Three of the four KB1 analogs
(KBS1, KBS3, and KBS4) showed inhibitory effects on the growth of S. epidermidis and enzyme inhibitory effects on saDHFR.
We performed structure–activity relationship (SAR) analysis
of active chemical compounds and observed a correlative relationship
among the IC50 values, interaction residues, and structure
scaffolds. In addition, the active chemical compounds (KB1, KBS3,
and KBS4) had no inhibitory effects on the growth of model enterobacteria
(E. coli BL21 and JM109 strains) and no toxic effects
on cultured mammalian cells (MDCK cells). Results obtained from Protein
Ligand Interaction Fingerprint (PLIF) and Ligand Interaction (LI)
analyses suggested that all of the active compounds exhibited potential
inhibitory effects on mutated saDHFR of the drug-resistant strains.
The structural and experimental information concerning these novel
chemical compounds will likely contribute to the development of new
antibiotics for both wild-type and drug-resistant S. aureus.
Asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes in the presence of a catalytic amount of novel squaramide-sulfonamide organocatalyst resulted in the corresponding addition products with high to excellent enantioselectivities. This is the first successful report illustrating an example of highly stereoselective reactions using a squaramide-sulfonamide organocatalyst.
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