The first antibiotic discovered was penicillin. Today, there is an entire class of antibiotics called penicillins, each of which interrupts the synthesis of bacterial cell walls. Penicillins themselves belong to a larger group of antibiotics characterized by having a specialized ring known as a beta-lactam in their chemical structure. The beta-lactam ring is similar in structure to a subunit on the peptidoglycan polymer in bacterial cell walls. An enzyme that links the peptidoglycan layers also binds the beta-lactam ring, disrupting linkage and cell wall integrity.
Many gram-negative bacteria possess genes for beta-lactamase enzymes that hydrolyze the beta-lactam ring, effectively providing multidrug resistance against entire groups of beta-lactam antibiotics. Beta-lactamase genes are encoded on the chromosome of some bacteria, but are also found on plasmids that can be horizontally transferred, when the genes are moved from one bacterium to another. One specific beta-lactamase effective against penicillin is penicillinase, an enzyme that catalyzes the hydrolysis of the beta-lactam ring of a penicillin drug.
Cephalosporin is a beta-lactam antibiotic with some resistance to beta-lactamase that is effective against gram-positive and some gram-negative bacteria. Since it is less susceptible to hydrolysis by beta-lactamase enzymes, it is effective against many bacteria that are resistant to penicillin. Cephalosporin, like penicillin, is a group of related antibiotics. Notably, many gram-negative bacteria, Neisseria gonorrhoeae for example, have developed resistance to the cephalosporins. In the fight to remain ahead of antibiotic resistance, several generations of cephalosporins have been created, and other beta-lactam antibiotics have been developed.
Another example of an antibiotic is imipenem, developed in the 1970s as an effective broad-spectrum antibiotic. Imipenem remains effective against many otherwise beta-lactam drug-resistant strains. inhibitors of these drugs tends to have little antibiotic effect by themselves, so they are often administered along with the beta-lactam itself. This combination disrupts the function of bacterial beta-lactamase enzyme, preventing it from hydrolyzing the beta-lactam ring of the concurrently administered antibiotic and circumventing bacterial resistance. There are many beta-lactamase inhibitors, and their effectiveness varies from one antibiotic to another.
Bacitracin and Isoniazid
Targeting the cell wall with an antibiotic is a common strategy because it is bactericidal and there are modes of action beyond the beta-lactams. One antibiotic, called bacitracin, targets enzymes on the cell membrane that transport the building blocks of the cell wall to the location of the growing wall. By interfering with these enzymes, bacitracin effectively inhibits cell wall synthesis, leading to cell death.
The drug isoniazid is specific to Mycobacterium tuberculosis, the causative agent of tuberculosis, and has a more complex action. Isoniazid acts as an antimetabolite by inhibiting the synthesis of a fundamental compound, mycolic acid, found specifically in the Mycobacterium cell wall. It is also commonly given to patients in combination with other antibiotic drugs. Before it is effective, a Mycobacterium enzyme must first activate isoniazid. A number of free radicals are produced during the process of activation, and these free radicals improve the functionality of the other coadministered antibiotics.
Bacitracin and isoniazid are both examples of antibiotics that disrupt the synthesis of bacterial cell walls. Other similarities, and some differences, highlight important considerations to antibiotic application. If used internally, bacitracin causes kidney damage. It is therefore used in preparations applied to the skin to keep wounds free of bacteria and to treat skin infections. Bacitracin is often used for a few days after tattoos are obtained to prevent the spread of infection and is commonly applied to superficial skin cuts. Isoniazid is taken internally. Both of these drugs are narrow-spectrum, attacking only a specific bacterium. Bacitracin is effective against only gram-positive bacteria. Isoniazid is only effective against members of the genus Mycobacterium.
The bacterial genome is unique from eukaryotic DNA in that many bacteria have a single circular chromosome. This chromosome is tightly coiled around itself like a tangled string. An enzyme, DNA gyrase, assists in uncoiling and relieving tension in the coiled chromosome to allow for replication and transcription. Since eukaryotes do not have DNA gyrase, it is a target for antibiotics. A quinolone is any of a large group of broad-spectrum antibiotics sharing a common chemical form that target bacterial DNA gyrase and are used in human and veterinary medicine for the treatment of bacterial infections. Disrupting DNA gyrase has a two-fold effect. By stopping DNA unwinding, quinolones are bacteriostatic in that they prevent replication. DNA must also be unwound for RNA polymerase enzymes to read and transcribe the code into messenger RNA. Preventing unwinding prevents messenger RNA synthesis and therefore new protein synthesis, conferring bactericidal properties to quinolones as well.
Most quinolones in use have a fluorine atom attached to their ring structure and are known as fluoroquinolones. Members of this group are widely used. Since they target a universal bacterial enzyme, they are broad-spectrum and effective against a wide array of gram-positive and gram-negative bacteria. They are commonly prescribed for the treatment of urinary tract infections, skin infections, and infections that have gone systemic.