An antibiotic is a chemical substance designed to kill or inhibit the growth of bacteria, forming the basis of modern infectious disease treatment. The term literally means “against life,” referring specifically to microbial life. These compounds revolutionized medicine following the discovery of penicillin by Alexander Fleming in 1928. Before antibiotics, common bacterial infections often proved fatal. Classifying these agents is necessary for clinical practice, guiding physicians in selecting the most effective treatment based on a pathogen’s identity and helping to manage the increasing threat of bacterial resistance.
Defining the Mechanisms of Action
Antibiotics are broadly categorized by the specific biological processes they target within a bacterial cell, known as the mechanism of action. This selective targeting is possible because bacterial cells possess structures and pathways distinct from human cells, such as a rigid external cell wall.
One major group interferes with the synthesis of this protective cell wall, leading to the structural collapse and death of the microorganism. Another focuses on the machinery responsible for manufacturing proteins, specifically the bacterial ribosome. Inhibiting this protein synthesis prevents the cell from producing the components necessary for growth and replication.
A third target involves the bacterial genetic material, where antibiotics interfere with DNA replication or transcription into RNA. Other groups disrupt the integrity of the cell membrane, causing the leakage of cellular contents, or interfere with essential metabolic pathways. For example, some antibiotics block the synthesis of folic acid, a compound required for making DNA and RNA building blocks.
Classes That Disrupt the Bacterial Cell Wall
Antibiotics that prevent cell wall construction primarily operate by inhibiting the cross-linking of peptidoglycan strands.
The Beta-lactams are the largest group, sharing a characteristic four-membered Beta-lactam ring. These drugs bind tightly to penicillin-binding proteins (PBPs), which are the transpeptidase enzymes responsible for linking peptidoglycan chains, thereby weakening the cell wall structure.
Penicillins, the original Beta-lactams, are effective against Gram-positive cocci but are often susceptible to destruction by bacterial beta-lactamase enzymes. Semi-synthetic penicillins like Ampicillin and Amoxicillin were developed to broaden the spectrum to include some Gram-negative organisms. Penicillinase-resistant versions, such as Methicillin, were created specifically to retain activity against Staphylococcus aureus strains that produce the destructive enzyme.
Cephalosporins represent a second large Beta-lactam group, classified into generations showing a progressive shift in activity. First-generation agents, such as Cefazolin, offer coverage against Gram-positive bacteria and are used for uncomplicated skin infections and surgical prophylaxis. Third-generation agents, exemplified by Ceftriaxone, expand coverage considerably against Gram-negative pathogens, suitable for complicated infections like meningitis. Fourth-generation cephalosporins, such as Cefepime, achieve a broad spectrum, including activity against Pseudomonas aeruginosa.
Carbapenems, including Meropenem, possess the broadest spectrum of all Beta-lactams and are often reserved for severe, multi-drug resistant infections. Their structure grants them stability against most beta-lactamase enzymes. Monobactams, such as Aztreonam, have a narrow spectrum, targeting only aerobic Gram-negative bacteria, and are valuable for patients with severe Beta-lactam allergies.
The Glycopeptide class, containing Vancomycin, works through a different mechanism. Vancomycin physically binds to the terminal D-Ala-D-Ala amino acid sequence of the peptidoglycan precursors. This binding prevents the transpeptidation enzyme from accessing its substrate, halting cell wall assembly. Due to its large molecular size, Vancomycin cannot penetrate the outer membrane of Gram-negative bacteria, limiting its use almost exclusively to serious Gram-positive infections, notably Methicillin-Resistant Staphylococcus aureus (MRSA).
Classes That Inhibit Protein Synthesis
Antibiotics that inhibit protein synthesis focus on the bacterial ribosome, which is composed of 30S and 50S subunits.
Tetracyclines, such as Doxycycline, are bacteriostatic agents that bind reversibly to the 30S ribosomal subunit. This action prevents the incoming aminoacyl-tRNA molecule from binding, blocking the addition of new amino acids to the growing protein chain. These broad-spectrum drugs are a treatment of choice for infections caused by atypical organisms like Rickettsia and Chlamydia.
Aminoglycosides like Gentamicin bind irreversibly to the 30S subunit, which is typically bactericidal. This binding causes a misreading of the messenger RNA template, resulting in the production of non-functional proteins. Aminoglycosides are potent against aerobic Gram-negative bacteria, such as Pseudomonas, but require intravenous or intramuscular administration for systemic infections due to poor oral absorption.
Macrolides, including Azithromycin and Erythromycin, are bacteriostatic drugs that target the 50S ribosomal subunit. They obstruct the nascent peptide exit tunnel, blocking the passage of the newly formed polypeptide chain. Macrolides are widely used for treating respiratory tract infections and atypical pneumonias.
Lincosamides, with Clindamycin, also bind to the 50S subunit and interfere with peptide bond formation, leading to premature dissociation of the protein chain. Clindamycin is a narrow-spectrum drug valued for its activity against Gram-positive bacteria and effectiveness against anaerobic organisms like Bacteroides fragilis. Oxazolidinones, represented by Linezolid, bind to the 50S subunit to prevent the formation of the 70S initiation complex. This distinct action makes Linezolid effective against drug-resistant Gram-positive pathogens, including MRSA and Vancomycin-Resistant Enterococci (VRE).
Classes Targeting DNA and Metabolic Pathways
Fluoroquinolones, such as Ciprofloxacin and Levofloxacin, are bactericidal agents that block the replication of bacterial DNA. They inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV, which manage the supercoiling and unlinking of DNA strands during replication. Fluoroquinolones are broad-spectrum and are often used for complicated urinary tract infections, severe respiratory infections, and infections involving Pseudomonas aeruginosa.
Rifamycins, including Rifampin, inhibit the initiation of RNA synthesis by binding to the bacterial enzyme DNA-dependent RNA polymerase. Rifampin targets the beta subunit of this enzyme, preventing the transcription of DNA into messenger RNA. This action halts the production of all bacterial proteins and is a cornerstone in multi-drug treatment regimens for tuberculosis.
The combination of Sulfonamides and Trimethoprim targets the bacterial metabolic pathway for producing folic acid, a necessary cofactor for DNA synthesis. Sulfonamides act as a competitive inhibitor by mimicking para-aminobenzoic acid (PABA), blocking the first step in the folate synthesis pathway. Trimethoprim then inhibits a later enzyme, dihydrofolate reductase. This strategy provides a synergistic effect, resulting in a highly effective combination often used for treating urinary tract infections and Pneumocystis pneumonia.