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Targocil: Novel antibiotics against Methicillin-resistant Staphylococcus aureus (MRSA)

• Novel antibiotic against MRSA with sub-micromolar MIC
• Potent small molecule inhibitor of wall teichoic acid (WTA) biosynthesis--an unexploited antibiotic target in Gram-positive bacteria
• Tested in murine model of endophthalmitis, and MSSA and MRSA isolates from cases of bacterial keratitis
• Total synthesis of Targocil, focus library of analogs, and comprehensive SAR data
• Target validated
• Non-toxic in mice at doses of 75 mg/kg


Keratitis is an infection of the cornea that occurs following injury or in association with contact lens wear, and S. aureus is a leading cause. Prof. Suzanne Walker has developed Targocil, a novel antibiotic against MRSA. In collaboration with Dr. Michael Gilmore of Massachusetts Eye and Ear Infirmary, they have shown the effects of Targocil in murine model of endophthalmitis, and also tested the efficacies of Targocil for a panel of MSSA and MRSA isolates from cases of bacterial keratitis. It was found that Targocil is more effective than vancomycin in blocking intracellular S. aureus growth. Moreover, resistant mutants that arise upon selection with these compounds are highly attenuated and show reduced epithelial cell binding and invasion.

Wall teichoic acid (WTA) is a cell surface glycopolymer found in Gram-positive bacteria, such as S. aureus. Currently an unexploited antibiotic target, WTA has been proposed as a virulence factor because knocking out the first gene (tarO) of the WTA biosynthetic pathway prevents infection. The Walker lab has shown that Targocil is an inhibitor of TarG, the transmembrane component of the two component ABC transporter that exports WTAs from the cytoplasm to the external surface of the bacterial membrane where they are attached to peptidoglycan. Targocil has minimally inhibitory concentration (MIC) of 0.3 uM. Targocil shows inhibitory activities against both methicillin-sensitive and methicillin-resistant S. aureus strains. The acute toxicity of Targocil has been tested: doses of 75 mg/kg administered via tail vein injection caused no adverse effects in mice after 24 h. Total synthetic method of Targocil and its analogs has been determined.

Intellectual Property Status: Patent(s) Pending

Applications

Approximately 1.7 million new cases and 100,000 deaths are caused by hospitals infections each year in the US. Methicillin-resistant Staphylococcus aureus (MRSA) is the best known and one of the most widespread examples of such pathogens. Glycopeptides, such as vancomycin, are the treatment of choice against MRSA. In 2006, sales of glycopeptides totaled $680M in seven largest pharmaceutical markets. Vancomycin-resistant strains have begun to appear and in such cases linezolid and daptomycin are used. Worldwide sales of linezolid (Zyvox, Pfizer) were $1.14B in 2009, and daptomycin (Cubicin, Cubist) generated $521M in sales in 2009.

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