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Eur J Med Chem. 2017 Oct 20;139:665-673. doi: 10.1016/j.ejmech.2017.08.039. Epub 2017 Aug 18.

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

Author information

1
Department of Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
2
Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA.
3
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
4
Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
5
Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 47907, USA. Electronic address: mseleem@purdue.edu.
6
Department of Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; Biomedical Sciences, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt. Electronic address: amayhoub@azhar.edu.eg.

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.

KEYWORDS:

Antibiotic drug resistance; Caenorhabditis elegans; Intracellular infection; MRSA; Methicillin-resistant Staphylococcus aureus; Pharmacokinetics

PMID:
28846967
PMCID:
PMC5911928
DOI:
10.1016/j.ejmech.2017.08.039
[Indexed for MEDLINE]
Free PMC Article

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