Carbapenems are a class of β-lactam antibiotics effective against severe bacterial infections. These medications are frequently reserved for treating infections caused by multidrug-resistant (MDR) bacteria, making them a last-resort option in many clinical scenarios. They are used for complicated infections affecting the abdomen, lungs, urinary tract, and skin. Like other β-lactams, their function is tied to disrupting the formation of the bacterial cell wall.
The Primary Target: Bacterial Cell Wall Construction
Every bacterium is encased in a protective layer known as the cell wall, which is primarily composed of peptidoglycan. This structure provides the cell with its shape and structural strength, preventing it from rupturing under internal osmotic pressure. The peptidoglycan layer is like a mesh-like scaffold that surrounds the bacterial cytoplasmic membrane. This layer is constantly being remodeled as the cell grows and divides.
The bacterial cell wall is an effective target for antibiotics because it is a feature that human cells lack. This distinction allows for selective toxicity, where the drug can attack the invading bacteria without harming the host’s cells. The absence of a cell wall in human biology means that medications designed to disrupt this structure have minimal impact on the patient’s cellular functions.
Peptidoglycan is a large polymer made of repeating sugar and amino acid components. It consists of long chains of two alternating sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to each NAM sugar is a short chain of amino acids. These peptide chains are then cross-linked to peptides on adjacent glycan strands, creating a strong, three-dimensional mesh. The thickness of this layer is substantially thicker in gram-positive bacteria compared to gram-negative bacteria.
Inhibition of Penicillin-Binding Proteins
The construction and maintenance of the peptidoglycan cell wall are managed by bacterial enzymes known as penicillin-binding proteins (PBPs). These proteins are responsible for the final steps of peptidoglycan synthesis, specifically the transpeptidation process. This process cross-links the peptide chains to form the strong, mesh-like structure of the cell wall.
Carbapenems exert their antibacterial effect by targeting and inhibiting these PBPs. The antibiotic molecule binds to the active site of the PBP enzymes, forming a stable complex that deactivates them. This action is similar to that of other β-lactam antibiotics, which mimic a component of the peptide chain, tricking the enzyme into binding with the drug. This binding is often irreversible, permanently disabling the enzyme.
Once the PBPs are inhibited, the bacterium can no longer properly synthesize or repair its peptidoglycan cell wall. As the cell attempts to grow, the activity of enzymes that break down the cell wall for remodeling continues without the corresponding construction from PBPs. This imbalance leads to a weakened, defective cell wall that cannot withstand the cell’s internal pressure. The compromised cell wall fails, causing the cell to lyse and die.
Structural Stability and Broad-Spectrum Activity
Carbapenems are effective against a wide range of bacteria due to their chemical structure. Like other β-lactams, they feature a core β-lactam ring but with molecular differences. In carbapenems, a carbon atom replaces the typical sulfur atom in the adjoining ring, and a double bond is introduced. This configuration alters the ring’s strain and reactivity, contributing to their potency.
A primary defense mechanism for bacteria is the production of enzymes called beta-lactamases, which inactivate β-lactam antibiotics like penicillin. The structure of carbapenems, however, makes them resistant to hydrolysis by the majority of these common beta-lactamase enzymes. A side chain with a trans configuration provides a structural shield that prevents these enzymes from cleaving the β-lactam ring.
This stability against enzymatic degradation allows carbapenems to remain active where other related antibiotics would be destroyed. This is a principal reason for their broad-spectrum activity, enabling them to target a wide variety of gram-positive and gram-negative bacteria. Because they bypass a common form of bacterial resistance, they are often reserved for serious infections, including those caused by bacteria that produce extended-spectrum beta-lactamases (ESBLs).
Mechanisms of Carbapenem Resistance
Despite the effectiveness of carbapenems, bacteria have developed mechanisms to resist their effects. The most significant of these is the production of enzymes known as carbapenemases. These are specialized beta-lactamases that have evolved the ability to hydrolyze and inactivate carbapenem antibiotics, which most other beta-lactamases cannot do.
Carbapenemases are categorized into different molecular classes, with classes A, B, and D being the most clinically relevant. Well-known examples include Klebsiella pneumoniae carbapenemase (KPC), which belongs to class A, and New Delhi metallo-beta-lactamase (NDM-1), a class B enzyme. The genes encoding these enzymes are often located on mobile genetic elements like plasmids, which allows them to be easily transferred between different bacteria, accelerating the spread of resistance. The global dissemination of bacteria producing KPC and NDM enzymes is a major public health concern.
Bacteria also employ other strategies to resist carbapenems. Some gram-negative bacteria reduce the drug’s entry by altering or reducing outer membrane porins, the channels antibiotics use to cross the membrane. Another method involves efflux pumps, which actively pump the antibiotic out of the cell before it can reach its PBP target. Finally, mutations in the PBP genes can change their structure so that carbapenems can no longer bind effectively.