Fi Lactamases

A new multicomponent reaction of nitro compounds with isocyanides gives ct-oxyimi-noamides, which are important for dnig synthesis such as cephiilosporin and fi-lactamase inhibitor fEq 6 65 Multicomponent reactions using isocyanides fUgi reacdoni is re-... 

Indicahons for combined therapy are now considered to be much fewer than originahy thought. There is also the problem of a chemical or physical incompahbility between two dmgs. Examples where combinahons have an important role to play in anhbacterial chemotherapy were provided earlier (sections 2.3 and 2.9) in which a fi-lactamase inhibitor and an appropriate j3-lactamase-labile penicillin form a single... 

Clavulanic Acid Class of fi-Lactamase Inhibitors. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important /8 lactamases, including penases and Richmond-Sykes types II, III, IV, V, VI (Bacteroides). 

Carbapenem-fi-Lactamase Inhibitors. Carbapenems are another class of natural product /8-lactamase inhibitors discovered about the same time as clavulanic acid... 

Scheme 7.4 Anchor fragments equipped with two thiol moieties (F-J) and thiol partner fragments (4-22) for DCC utilizing thiol-disulfide exchange and targeting metal lo-fi -lactamase.

Scheme 7.5 DCC enzyme inhibitor discovery and optimization protocol targeting metal lo-fi-lactamase.

Fig. 8. Cleavage of the fluorescent reporter CCF2-AM in cells expressing fi-lactamase...

Fig. 9. Effect of an 20-h cis- or trans-DDP treatment on carbachol-inducible fi-lactamase expression in Jurkat cells. The gene expression was determined by measuring the cleavage of...

One of the most potent and physiologically irreversible mechanisms of antibiotic resistance is via chemical destruction of the antibiotic warhead or scaffold. This destruction can occur through several mechanisms, but hydrolytic approaches predominate (Fig. 4). Resistance to the highly important fS-lactam antibiotics by fi-lactamases is the archetype of this class. The fS-lactams include the natural product penicifhn and cephalos... 

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. 

The degree to which this is a problem can be appreciated by a screen of 70,563 molecules to discover inhibitors of the enzyme AmpC fi-lactamase [25], Of the 1,274 hits, 1,213 turned out to be aggregators - more than 95% Even worse, these compounds often display structure-activity relationships (SAR), and the effect can persist even at fairly low concentrations. Recently, a series of cruzain inhibitors with IC50 values as low as 200 nM were reported, but follow-up studies determined... 

Figure 7.12. Chemical modifications of penicillin are responsible for penicillinase-resistance and improved spectrum of activity. Penicillinases (also called fi-lactamases because they inactivate cephalosporins and other fi-lactams as well) inactivate penicillin by cleaving the fi-lactam ring. Bulky chemical groups are linked to penicillinase-resistant penicillins. The bulky group prevents penicillin from entering the active site of penicillinase, but does not interfere with binding to PBPs on the bacterial cell surface. Narrow spectrum penicillins are unable to pass through the outer membrane of Gram-negative bacteria. Broad spectrum penicillins are more hydrophilic and are thus able to penetrate the aqueous pores of the outer membrane of Gramnegative bacteria.

Fig. 3.35 The presence of P-lactamase conformed 47 to hydrogelator 48 a NaHC03, DMF b TFA, anisole, CH2CI2 c fi-lactamase, pH = 8.0...

The design, synthesis, and biological properties of a new class of chiral boronic acids that effectively target two representative fi-lactamases found in nosocomial... 

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