Discovery of MC-02,331, a new cephalosporin exhibiting potent activity against methicillin-resistant Staphylococcus aureus.


A systematic approach toward building activity against methicillin-resistant staphylococci into the cephalosporin class of beta-lactam antibiotics is described. Initial work focused on finding the optimal linkage between the cephem nucleus and a biphenyl pharmacophore, which established that a thio linkage afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacophore afforded iodophenylthio analog MC-02,002, which although highly potent against MRSA, was also highly bound to serum proteins. Further work to decrease serum protein binding showed that replacement of the iodo substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous solubility. Solubility was enhanced by incorporation of a second positively-charged group into the 7-acyl substituent. Such derivatives (MC-02,171 and MC-02,306) lacked sufficient stability to staphylococcal beta-lactamase enzymes. The second positive charge was incorporated into the cephem 3-substituent in order to utilize the beta-lactamase-stable aminothiazolyl(oximino)acetyl class of 7-substituents. These efforts culminated with the discovery of bis(isothiouroniummethyl)phenylthio analog MC-02,331, whose profile is acceptable with respect to potency against MRSA, serum binding, aqueous solubility, and beta-lactamase stability.

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@article{Hecker1998DiscoveryOM, title={Discovery of MC-02,331, a new cephalosporin exhibiting potent activity against methicillin-resistant Staphylococcus aureus.}, author={Scott J Hecker and Insook Cho and Tomasz W Glinka and Z . J . Zhang and Mary E Price and Ving J. Lee and Burton G Christensen and Adam Boggs and Suzanne Chamberland and François Malouin and Thomas R Parr and Thangavelu Annamalai and Jocelyne Blais and Elaine Bond and L W Case and C W H Chan and Jan Crase and Rachel Frith and David C. Griffith and Laurie Harford and Ni Liu and Maria Ludwikow and Kristina Mathias and Diane Rea and Robert M. Williams}, journal={The Journal of antibiotics}, year={1998}, volume={51 8}, pages={722-34} }