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.
The promising activity of phenylthiazoles against multidrug-resistant bacterial pathogens, in particular MRSA, has been hampered by their limited systemic applicability, due to their rapid metabolism by hepatic microsomal enzymes, resulting in short half-lives. Here, we investigated a series of phenylthiazoles with alkynyl side-chains that were synthesized with the objective of improving stability to hepatic metabolism, extending the utility of phenylthiazoles from topical applications to treatment of a more invasive, systemic MRSA infections. The most promising compounds inhibited the growth of clinically-relevant isolates of MRSA in vitro at concentrations as low as 0.5 μg/mL, and exerted their antibacterial effect by interfering with bacterial cell wall synthesis via inhibition of undecaprenyl diphosphate synthase and undecaprenyl diphosphate phosphatase. We also identified two phenylthiazoles that successfully eradicated MRSA inside infected macrophages. In vivo PK analysis of compound 9 revealed promising stability to hepatic metabolism with a biological half-life of ∼4.5 h. In mice, compound 9 demonstrated comparable potency to vancomycin, and at a lower dose (20 mg/kg versus 50 mg/kg), in reducing the burden of MRSA in a systemic, deep-tissue infection, using the neutropenic mouse thigh-infection model. Compound 9 thus represents a new phenylthiazole lead for the treatment of MRSA infections that warrants further development.
The
narrow antibacterial spectrum of phenylthiazole antibiotics was expanded
by replacing central thiazole with a pyrazole ring while maintaining
its other pharmacophoric features. The most promising derivative,
compound 23, was more potent than vancomycin against
multidrug-resistant Gram-positive clinical isolates, including vancomycin-
and linezolid-resistant methicillin-resistant Staphylococcus
aureus (MRSA), with a minimum inhibitory concentration
(MIC) value as low as 0.5 μg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic
carbapenem-resistant strains, such as Acinetobacter
baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition
to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular
burden of both Gram-positive and Gram-negative pathogenic bacteria.
Compound 23 cleared 90% of intracellular MRSA and 98%
of Salmonella enteritidis at 2×
the MIC. Moreover, preliminary pharmacokinetic investigations indicated
that this class of novel antibacterial compounds is highly metabolically
stable with a biological half-life of 10.5 h, suggesting a once-daily
dosing regimen.
Thirty-two new naphthylthiazole
derivatives were synthesized with
the aim of exploring their antimicrobial effect on multidrug-resistant
Gram-positive bacteria. Compounds 25 and 32, with ethylenediamine and methylguanidine side chains, represent
the most promising derivatives, as their antibacterial spectrum includes
activity against multidrug-resistant staphylococcal and enterococcal
strains. Moreover, the new derivatives are highly advantageous over
the existing frontline therapeutics for the treatment of multidrug-resistant
Gram-positive bacteria. In this vein, compound 25 possesses
three attributes: no bacterial resistance was developed against it
even after 15 passages, it was very efficient in targeting intracellular
pathogens, and it exhibited a concentration-dependent ability to disrupt
the preformed bacterial biofilm.
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