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

J Antibiot (Tokyo). 1998 Aug;51(8):722-34. doi: 10.7164/antibiotics.51.722.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Bacterial Proteins*
  • Carrier Proteins / metabolism
  • Cephalosporins / chemistry*
  • Cephalosporins / metabolism
  • Cephalosporins / pharmacology
  • Hexosyltransferases*
  • Humans
  • Lactams / chemistry*
  • Lactams / metabolism
  • Lactams / pharmacology
  • Male
  • Methicillin Resistance
  • Mice
  • Microbial Sensitivity Tests
  • Muramoylpentapeptide Carboxypeptidase / metabolism
  • Penicillin-Binding Proteins
  • Peptidyl Transferases*
  • Staphylococcus aureus / drug effects*
  • Structure-Activity Relationship


  • Bacterial Proteins
  • Carrier Proteins
  • Cephalosporins
  • Lactams
  • MC-02,331
  • Penicillin-Binding Proteins
  • Peptidyl Transferases
  • Hexosyltransferases
  • Muramoylpentapeptide Carboxypeptidase