Structure-activity relationship of new 2-substituted penem antibiotics.
The antibacterial activities of three new penems with 4-hydroxyprolinamide, 1-prolinamide and N-methyl-N-2-propionamide substituents, respectively, in position 2 and of their stereoisomers were examined against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa. All substitutes conferred a broad antibacterial spectrum on the penem moiety. Changes in stereoisomerism selectively improved the activity against E. coli, S. aureus or enterococci. The structure-activity relationships of each compound were discussed in relation to minimum inhibitory concentrations, penicillin-binding protein (PBP) affinity and outer membrane permeability coefficient in E. coli. In this microorganism, PBP 2 was the target for all compounds. Changes in stereoisomerism influenced the affinity for PBPs 1A/B and 2. All antibiotics easily permeated the outer membrane of E. coli and, within each group of compounds, the penetration rate correlated with the antibacterial activity.
Fontana
R
R
Istituto di Microbiologia, Università di Verona, Italy.
Altamura
M
M
Arcamone
F
F
Cornaglia
G
G
Morandotti
G
G
Sperning
R
R
Valisena
S
S
Satta
G
G
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D007769:Lactams; D008826:Microbial Sensitivity Tests; D010539:Permeability; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D007769:Lactams