Carbapenems: past, present, and future

Abstract

In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. 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. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. 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.

Fig. 1.

(A) Chemical structures of olivanic acid, clavulanic acid, and thienamycin. (B) Clinically available carbapenems, as well as cilastatin and betamipron. Previous identifiers of compounds are listed below each name.

Fig. 2.

(A) A 1-β-methyl (red) increases resistance to DHP-I. (B) The pyrrolidine ring (red) increases stability and spectrum. (C) Penicillin, cephalosporin, and carbapenem backbones. Carbapenem has a five-membered ring, as does penicillin, but it has a carbon at C-1 instead of sulfur. (D) Most carbapenems have a hydroxyethyl off C-7. (E) The R configuration of the hydroxyethyl increases the β-lactam's potency. (F) The trans configuration of carbapenems at the C-5—C-6 bond increases their potency compared to penicillins and cephalosporins.

Fig. 3.

(A) Enzymatic scheme for β-lactam inhibition of PBPs. In this reaction scheme, E₁ corresponds to the PBP, S to the carbapenem, E₁:S to the Michaelis complex, E₁-S to the inactivated PBP, and P to the inactivated β-lactam product; k₁, k₋₁, k₂, and k₃ represent the on, off, acylation, and deacylation rate constants, respectively. (B) Enzymatic scheme for carbapenem inhibition and hydrolysis by class A, C, and D β-lactamases. In this reaction scheme, E₂ corresponds to the β-lactamase, S to the carbapenem, E₂:S to the Michaelis complex, E₂-S (Δ²) to the acyl-enzyme, E₂-T (Δ¹) to the tautomerized carbapenem, and P to the inactivated β-lactam product; k₁, k₋₁, k₂, and k₃ represent the on, off, acylation, and deacylation rate constants, respectively. The conversion of E₂-S to E₂-T represents the biphasic nature of carbapenem hydrolysis, potentially due to tautomerization of the pyrroline double bond, which may or may not play a role in carbapenemase activity.

Fig. 4.

Crystal structures of the carbapenemase, KPC-2 (Protein Data Bank [PDB] identifier 2OV5), present in the periplasm, P. aeruginosa porin, OprD (substrate binding loops highlighted in yellow) (PDB identifier 2ODJ) present in the outer membrane, P. aeruginosa efflux pump components, MexA, MexB, and OprM (PDB identifiers 1VF7, 2V50, and 3D5K), spanning the inner membrane and periplasmic and outer membranes, and P. aeruginosa PBP3 (PDB identifier 3PBN), anchored to the inner membrane.

Fig. 5.

(A) Mechanism of carbapenem hydrolysis by CphA. (B) Subclass B1 and B3 metallo-β-lactamase active sites. (C) Stabilization of the anionic intermediate in GOB-18.

Fig. 6.

(A) The mechanism of carbapenem tautomerization. (B) The proposed mechanism for hydroxyethyl elimination in class A and C β-lactamases.

Fig. 7.

(A) TEM-1 and imipenem (PDB identifier 1BT5). (B) TEM-1 Asn132Ala and imipenem (PDB identifier 1JVJ).

Fig. 8.

(A) BlaC with ertapenem preisomerization (PDB identifier 3M6B). (B) BlaC with ertapenem postisomerization (PDB identifier 3M6H).

Fig. 9.

Novel carbapenems.