Antibacterial Therapy

This is an antagonistic situation because the antibiotic will less efficiently be absorbed in the presence of the antacid.

ANTIBACTERIAL THERAPY

The goal of antibacterial therapy is to be selectively toxic. This means that the drug is toxic to the organism but not to the host. It generally also means that the drug will harm prokaryotes but not eukaryotes. Every antibacterial drug has a specific mode of action against the organism. It can attack the cell wall, the plasma membrane, the ribosomes, DNA synthesis, or the metabolic pathways of the organism.

Examples of drugs that attack the cell wall synthesis include penicillins and bacitracin. Protein synthesis in the ribosomes is affected by aminoglycosides, macrolides, and lincosamides. Membranes are disrupted by polymyxin B and daptomycin. Nucleic acid synthesis is affected by fluoroquinolones and rifamycin. Folic acid synthesis is affected by trimethoprim and sulfonamides. There are also drugs that affect the synthesis of ATP and mycolic acid.

The first antibiotic known in modern times was penicillin. It belongs to the beta-lactam class of antibiotics, which also includes monobactams, carbapenems, and cephalosporins. Beta-lactams affect the synthesis of the bacterial cell wall because it prevents cross-linking of the peptidoglycan layer. These tend to work better on grampositive organisms.

Penicillin is a natural antibiotic. Amoxicillin and ampicillin are aminopenicillins synthesized from natural penicillin. Methicillin is also semi-synthetic. Cephalosporins are also beta-lactams with slightly different chemical properties. It is less resistant to the beta-lactamase enzymes that some organisms secrete. There are many generations of cephalosporins that differ in their spectrum of activity. First generation cephalosporins are the most broadly acting of these drugs, while a new fifth generation cephalosporin is only active against MRSA or methicillin-resistant Staphylococcus aureus. Aztreonam is the only monobactam and it is only active against gram-negative organisms.

Vancomycin is a glycopeptide that also inhibits bacterial cell wall biosynthesis. It is a bactericidal drug often used to treat MRSA. It binds to precursors that make the cell wall, preventing cell wall synthesis and killing the organism. It cannot kill gramnegative bacteria because it cannot get through the outer membrane of these organisms.

Bacitracin was once harvested from the Bacillus subtilis organism. It affects the cell membrane and prevents peptidoglycan precursor molecules from getting to the outside of the cell membrane. This is how it blocks cell wall synthesis. It is used mainly topically to kill Staphylococcus and Streptococcus but is toxic to the kidneys if given orally.

There are drugs that rely on the fact that the ribosomes in prokaryotes are different from those seen in eukaryotes. Aminoglycosides are antibiotics that do this by blocking the ability of ribosomes to proofread the proteins being made. Abnormal proteins get made quite easily, which kills the cells. These are broad-spectrum antibiotics such as streptomycin, gentamicin, and neomycin. The problem with these drugs is that they are ototoxic and cause deafness, neurotoxic, and nephrotoxic, causing kidney damage. There is a narrow range in the bloodstream where the drug is effective without being toxic.

Tetracycline binds to the small subunit of the ribosomes and is bacteriostatic by blocking the activity of transfer RNA. There are natural tetracyclines and semisynthetic tetracyclines. The danger to these drugs is discoloration of the teeth, liver toxicity, and phototoxicity so that sunburn can easily occur while using the drug.

There are other drugs that bind to the large subunit of the ribosomes. This is true of the macrolides, which are bacteriostatic and broad-spectrum antibiotics. The first of these drugs was erythromycin. A semisynthetic related drug is azithromycin. They block the elongation of proteins by blocking some peptide bonds, keeping them from forming. Azithromycin is the better drug because it has a considerably longer half-life and the ability to be taken in very short courses.

The lincosamides like clindamycin and lincomycin are related to macrolides and also bind to the larger ribosomal subunit. They also block some peptide linkages. Chloramphenicol is distinct but also binds to the larger ribosomal subunit, blocking peptide bonding. It is both a natural and synthesized antibiotic, being the first to be

mass-produced. It has several adverse effects, mainly that it blocks the activity of the bone marrow to make blood cells. For this reason, it is not often used. Aplastic anemia from this drug is irreversible and very dangerous.

Linezolid is a newer antibiotic that binds to the larger subunit of the ribosomes. It acts uniquely by preventing the 50S and 30S ribosomal subunits to bind together, preventing protein synthesis. It keeps the polypeptide chain from moving from the A site to the P site in the ribosomal complex.

There are drugs that specifically target the bacterial cell membrane. These include polymyxins, such as polymyxin B. These act like detergents to disrupt the gram-negative outer membrane, killing the bacteria. These can be nephrotoxic and neurotoxic so they are used topically in antibiotic ointment. Oral colistin is used to decontaminate the bowel; it is used intravenously as a last resort when there is a serious infection. Daptomycin is a lipopeptide that disrupts the cell membrane, killing gram-positive organisms. The main side effect of daptomycin is muscle aches.

Some antibacterial drugs will block nucleic acid synthesis. Metronidazole can do this for bacterial and protozoal infections. DNA replication is affected. Rifampin targets RNA polymerase which, as you remember, is different between bacteria and eukaryotes. Rifampin is used with other antibiotics to kill tuberculosis-causing organisms. The biggest risk is hepatotoxicity.

Fluoroquinolones were originally made from nalidixic acid. Both levofloxacin and ciprofloxacin inhibit DNA gyrase in the microorganism. There are many side effects, including those on the heart, glucose metabolism, nerves, skin, and tendons. These drugs will treat both gram-positive and gram-negative organisms.

Drugs can also inhibit bacterial cell metabolism. This is true of sulfonamides, which block folic acid synthesis, which in turn affects nucleic acid synthesis. Sulfonamides are bacteriostatic and are not harmful to humans, who get folic acid from the diet. Allergic reactions to these drugs are common. Sulfones are related drugs used to help people with leprosy or Hansen’s disease. Trimethoprim inhibits another enzyme in this synthetic pathway. This is why trimethoprim and sulfonamides are considered synergistic and bactericidal when used together.