The Core Mechanism: Inhibiting Cell Wall Synthesis
Cephalosporins are a crucial class of antibiotics known for their bactericidal (bacteria-killing) properties [1.2.9]. Their primary function is to disrupt the creation of the bacterial cell wall, a structure essential for the bacterium's survival and integrity, especially in Gram-positive bacteria [1.3.4]. The key component of this wall is peptidoglycan, a polymer that provides structural strength [1.3.7].
The mechanism of action is centered on the drug's β-lactam ring [1.3.2]. This chemical structure mimics the D-Ala-D-Ala-moiety, which is a substrate for enzymes known as penicillin-binding proteins (PBPs) [1.2.9, 1.6.5]. PBPs, such as peptidoglycan transpeptidases, are responsible for the final step in peptidoglycan synthesis: cross-linking the peptide chains to create a strong, stable mesh-like layer [1.3.3].
When a cephalosporin is present, its β-lactam ring binds to the active site of these PBPs, effectively acylating them [1.3.5]. This binding is irreversible and inactivates the enzyme [1.3.6]. Without functional PBPs, the bacterium cannot complete the cross-linking of its peptidoglycan layer. As the bacterium continues to grow and divide, it is unable to build a structurally sound cell wall, leading to the formation of a weakened cell wall and, eventually, cell lysis (rupture) and death due to osmotic pressure [1.3.4, 1.3.6].
Targeting Penicillin-Binding Proteins (PBPs)
The effectiveness of a cephalosporin is directly related to its affinity for specific PBPs within a bacterial species [1.4.2]. Different cephalosporins may have varying affinities for different PBPs, which contributes to their spectrum of activity [1.4.2]. For instance, the ability of ceftriaxone to saturate essential PBPs explains its high in-vivo efficacy [1.4.4]. Bacteria can develop resistance by altering their PBPs, reducing the drug's ability to bind. This is a key mechanism of resistance in organisms like Methicillin-resistant Staphylococcus aureus (MRSA), where an altered PBP prevents most beta-lactams from working effectively [1.3.2]. Only fifth-generation cephalosporins, like ceftaroline, have been specifically designed to bind to this altered PBP in MRSA [1.5.6].
Cephalosporin Generations and Spectrum of Activity
Cephalosporins are categorized into five generations, with each successive generation generally offering a broader spectrum of activity against Gram-negative bacteria, sometimes at the cost of reduced Gram-positive coverage [1.5.7].
- First Generation: Primarily active against Gram-positive bacteria like Staphylococcus and Streptococcus, with limited Gram-negative coverage [1.5.7]. They are often used for skin and soft tissue infections [1.5.6].
- Second Generation: Offer expanded Gram-negative coverage (e.g., H. influenzae, Neisseria) while retaining good Gram-positive activity. Some, like the cephamycins (e.g., cefoxitin, cefotetan), have activity against anaerobic bacteria [1.5.6, 1.5.8].
- Third Generation: Show significantly increased activity against a wide range of Gram-negative bacteria and many are able to cross the blood-brain barrier, making them useful for treating meningitis [1.5.6]. Some (like ceftazidime) are active against Pseudomonas aeruginosa [1.5.6].
- Fourth Generation: Cefepime is a broad-spectrum agent with the Gram-positive activity similar to the first generation and the strong Gram-negative activity of the third generation, including Pseudomonas aeruginosa [1.5.6]. It is also more resistant to certain beta-lactamases [1.5.9].
- Fifth Generation: This generation's defining feature is its activity against MRSA [1.5.8]. Ceftaroline is a notable example, covering MRSA and other resistant Gram-positive organisms, but it does not cover Pseudomonas aeruginosa [1.5.6].
| Generation | Gram-Positive Activity | Gram-Negative Activity | Key Features & Examples |
|---|---|---|---|
| First | Excellent | Limited (e.g., E. coli, K. pneumoniae) | Cefazolin, Cephalexin; Used for skin infections, surgical prophylaxis [1.5.6, 1.5.7]. |
| Second | Good | Expanded (adds H. influenzae, Neisseria) | Cefuroxime, Cefoxitin; Good for respiratory infections, some anaerobic coverage [1.5.6]. |
| Third | Variable (often less than 1st/2nd) | Broad | Ceftriaxone, Ceftazidime; Crosses blood-brain barrier, Pseudomonas coverage (ceftazidime) [1.5.6]. |
| Fourth | Good (like 1st gen) | Broad (including Pseudomonas) | Cefepime; Broad-spectrum, stable against many β-lactamases [1.5.6, 1.5.9]. |
| Fifth | Excellent (including MRSA) | Broad (but not Pseudomonas) | Ceftaroline, Ceftobiprole; Unique activity against MRSA and other resistant bacteria [1.5.6, 1.5.8]. |
Mechanisms of Bacterial Resistance
Despite the effectiveness of cephalosporins, bacteria have evolved several mechanisms to resist their action:
- Enzymatic Degradation: The most common resistance mechanism is the production of β-lactamase enzymes [1.6.3]. These enzymes hydrolyze (break) the β-lactam ring of the antibiotic, inactivating it before it can reach the PBP target [1.3.6]. Extended-spectrum β-lactamases (ESBLs) are particularly problematic as they can inactivate a wide range of cephalosporins [1.6.5].
- Alteration of Target Site: Bacteria can alter the structure of their PBPs through genetic mutation [1.6.4]. This change reduces the binding affinity of the cephalosporin to the PBP, rendering the drug less effective or completely ineffective [1.6.2]. This is the primary mechanism of resistance in MRSA [1.3.2].
- Reduced Permeability: Gram-negative bacteria have an outer membrane that antibiotics must cross to reach the PBPs in the periplasmic space [1.6.8]. Bacteria can develop resistance by modifying or reducing the number of porin channels in this membrane, thereby restricting the drug's entry [1.6.5, 1.6.6].
- Efflux Pumps: Some bacteria can actively pump the antibiotic out of the cell before it can reach its target [1.6.4]. This mechanism can contribute to resistance against multiple types of drugs, including cephalosporins [1.6.5].
Conclusion
The mechanism of action of cephalosporins is a well-defined process of bactericidal activity. By irreversibly inhibiting the penicillin-binding proteins essential for peptidoglycan synthesis, they effectively destroy the integrity of the bacterial cell wall, leading to cell death. The evolution of these drugs across five generations has provided clinicians with tools to combat a shifting landscape of bacterial pathogens. However, the concurrent rise of resistance mechanisms, such as β-lactamase production and PBP modification, underscores the ongoing challenge in infectious disease management and the need for continued antibiotic stewardship and development. For more in-depth information on pharmacology, consider resources like the NCBI StatPearls bookshelf.
