Penicillin derivatives lactamase inhibition

Penicillins and cephalosporins are antibiotics (E 5.2) used in medicine. They inhibit cell wall formation in bacteria. The naturally occurring penicillins and cephalosporins are inactivated, e.g., by bacterial j8-lactamases and by the acid in the stomach. 6-Aminqpenicillanic acid obtained by enzymatic hydrolysis of penicillin G, is commercially converted to semi-synthetic penicillins which are stable to acids and/or resistant to penicillin-j8-lactamase and may possess a broader spectrum of antibiotic activity in comparison to the naturally occurring penicillins. Also semisynthetical cephalosporin C derivatives are used in medicine. 

Certain penicillins and penam derivatives have the ability to inhibit the /3-lactamase enzyme, and can provide a variable degree of protection to susceptible /3-lactam antibiotics... 

It is formed by acylases that cleave off the side chain of the penicillins, and can also be obtained by the selective chemical cleavage of the amide, leaving the lactam intact. After this, 6-APA can be easily acylated by any carboxylic acid, and this has yielded literally thousands of semisynthetic penicillins in the past 30 years, many showing improved stability and activity. Some of them are lactamase resistant (methicillin (9.41), oxacillin (9.42) and its halogenated derivatives), whereas others are broad-spectrum antibiotics, like the orally active ampicillin (9.43), which also inhibits Gramnegative bacteria but is sensitive to lactamase. Carbenicillin (9.44) is particularly active against Pseudomonas and Proteus infections, which are unaffected by natural penicillins. Piperacillin (9.45), a broad-spectrum compound, is spectacularly active against Pseudomonas. 

Because they cause prolonged inactivation of certain fi-lactamases. class I inhibitors ate particularly useful in combination with extended-spectrum, lactamase-sen.sitive penicillins to treat infections caused by lactamase-producing bacteria. Three such inhibitors, clavulanic acid, sulbactam, and tazobactam. are currently marketed in the United States for this purpose. A class II inhibitor, the carbapenem derivative imipenem. has potent antibacterial activity in addition to its ability to cause transient inhibition of some /3-lactamases. Certain antibacterial cephalosporins with a leaving group at the C-3 position can cause transient inhibition of lactamases by forming stabilized acylenzyme intermiediates. These are discu.ssed more fiilly below in this chapter. 

Further observations were published concerning the mechanism of action of the penicillins.Data support the concept that the P-lactam antibiotics inhibit a transpeptidase essential for a cross-linking reaction in bacterial cell-wall synthesis. Transpeptidase derived from cell-free systems of E. coli, like that from aureus, is inactivated by penicillins. Thus, the possession of cellular permeability barriers in addition to P-lactamase productive capacity apparently tends to protect greun-negative bacteria from lethal attack by P-lactam antibiotics.33... 

Boronic acid derivatives have been shown to inhibit -lactamases [168]. The boronic acid function, which is isoelectronic with a protonated carboxyl group, is presumed to block enzymatic activity by forming a stable tetrahedral borate complex with the active serine residue. Boronic acids 319, structurally related to penicillin G and methicillin, were synthesised in three steps from dibutyl iodomethaneboronate [169] (Scheme 97). They are inhibitors of P-lactamase I from B. cereus. There are presently no reports of boronic acid derivatives acting as inhibitors of bacterial D,D-peptidases. 

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