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.
Microcide Pharmaceuticals, Inc., Mountain View, CA 94043, USA.
S J
SJ
Hecker
I S
IS
Cho
T W
TW
Glinka
Z J
ZJ
Zhang
M E
ME
Price
V J
VJ
Lee
B G
BG
Christensen
A
A
Boggs
S
S
Chamberland
F
F
Malouin
T R
TR
Parr
T
T
Annamalai
J
J
Blais
E L
EL
Bond
L
L
Case
C
C
Chan
J
J
Crase
R
R
Frith
D
D
Griffith
L
L
Harford
N
N
Liu
M
M
Ludwikow
K
K
Mathias
D
D
Rea
R
R
Williams
D000818:Animals; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002511:Cephalosporins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006602:Hexosyltransferases; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D007769:Lactams; C114882:MC-02,331; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase