Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis

Abstract

The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin-resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds’ lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages.

Identification of a Phenylthiazole Small Molecule with Dual Antifungal and Antibiofilm Activity Against Candida albicans and Candida auris

“…albicans P60002. Previously these small molecules were extensively investigated as antibacterial agents against drug-resistant staphylococci and enterococci 28–35 . Interestingly, the most potent phenylthiazole compounds with antibacterial activity were generally less effective against C .…”

“…Compounds were synthesized and characterized as described in previous reports. The synthetic schemes for compounds 1 - 23 29,31,35,48,49 , compounds 24 - 31 28 , and compounds 32 - 85 30,34,50,51 are presented in the supplementary information file. Compounds were prepared as stock 10 mg/mL or 1 mg/mL solutions in dimethyl sulfoxide (DMSO).…”

Peptidoglycan pathways: there are still more!

“…109,110 This criteria is clinically important, as it would affect the size of the dosing regimen necessary for patients. 111,112 Through the more than 400 published phenylthiazole derivatives, 110,[113][114][115][116][117][118][119][120][121][122][123][124][125][126] the SAR of this class of compounds has become well dened (Fig. 4).…”

“…5). 113 Later on, a detailed metabolite analysis was completed and this indicated the presence of an additional metabolic so spot at the butyl benzylic carbon. 125 Addressing this limitation, replacing the methylene so spot with oxygen 125 or acetylenyl 114 moieties or undergoing replacement with t-butyl, 117 has yielded phenylthiazoles with even more pronounced stability with respect to the hepatic metabolism ( Fig.…”

Synthesis and antibacterial activities of novel pleuromutilin derivatives

“…Multidrug resistance bacteria are one of major threats to human health, especially Escherichia coli , Staphylococcus aureus , Pseudomonas aeruginosa , Mycobacterium tuberculosis , and Streptococcus pneumonia . Without ascending the discovery and approval of new antibiotics and introducing new scaffolds with the ability to combat the rapid rise in bacterial resistance to traditional classes of antibiotics, we risk moving back toward the pre‐antibiotic era …”