clavuligerus, the first clinically available β-lactamase inhibitor ( 25), and (ii) thienamycin (compound 3) from Streptomyces cattleya ( Fig. Shortly thereafter, two superior β-lactamase inhibitors were discovered: (i) clavulanic acid (compound 2) from S. Due to chemical instability and poor penetration into the bacterial cell, the olivanic acids were not further pursued ( 192). Olivanic acids possess a “carbapenem backbone” (a carbon at the 1 position, substituents at C-2, a C-6 ethoxy, and sp 2-hybridized C-3) and act as broad-spectrum β-lactams ( 25, 27, 199). 1) were natural products produced by the Gram-positive bacterium Streptomyces clavuligerus. By 1976, the first β-lactamase inhibitors were discovered these olivanic acids (compound 1 in Fig. In the late 1960s, as bacterial β-lactamases emerged and threatened the use of penicillin, the search for β-lactamase inhibitors began in earnest ( 38, 199). In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.
#Pbp3 pdb how to#
Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to β-lactamase inhibition. Several recent studies clearly show that resistance to carbapenems is increasing throughout the world ( 35, 64, 73, 123, 151, 155, 173, 200). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs ( 189). As a result, they are often used as “last-line agents” or “antibiotics of last resort” when patients with infections become gravely ill or are suspected of harboring resistant bacteria ( 23, 174– 176, 229). Of the many hundreds of different β-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.Ĭarbapenems play a critically important role in our antibiotic armamentarium. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. We describe the initial discovery and development of the carbapenem family of β-lactams. This “value-added feature” of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as “slow substrates” or inhibitors of β-lactamases, and still target penicillin binding proteins.
In this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our antimicrobial armamentarium.
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