14.5: Other Antibiotics

Learning Objectives

• Explain how polymyxins inhibit membrane function.
• Contrast rifampin and fluoroquinolones in their actions to block nucleic acid synthesis.
• Summarize metabolite inhibitors and why they have high selective toxicity.

Inhibitors of Membrane Function

A small group of antibacterials target the bacterial membrane as their mode of action (Table \(\PageIndex{4}\)). The polymyxins are natural polypeptide antibiotics that were first discovered in 1947 as products of Bacillus polymyxa; only polymyxin B and polymyxin E (colistin) have been used clinically. They are lipophilic with detergent-like properties and interact with the lipopolysaccharide component of the outer membrane of gram-negative bacteria, ultimately disrupting both their outer and inner membranes and killing the bacterial cells. Unfortunately, the membrane-targeting mechanism is not a selective toxicity, and these drugs also target and damage the membrane of cells in the kidney and nervous system when administered systemically. Because of these serious side effects and their poor absorption from the digestive tract, polymyxin B is used in over-the-counter topical antibiotic ointments (e.g., Neosporin), and oral colistin was historically used only for bowel decontamination to prevent infections originating from bowel microbes in immunocompromised patients or for those undergoing certain abdominal surgeries. However, the emergence and spread of multidrug-resistant pathogens has led to increased use of intravenous colistin in hospitals, often as a drug of last resort to treat serious infections. The antibacterial daptomycin is a cyclic lipopeptide produced by Streptomyces roseosporus that seems to work like the polymyxins, inserting in the bacterial cell membrane and disrupting it. However, in contrast to polymyxin B and colistin, which target only gram-negative bacteria, daptomycin specifically targets gram-positive bacteria. It is typically administered intravenously and seems to be well tolerated, showing reversible toxicity in skeletal muscles.

Table \(\PageIndex{4}\): Drugs That Inhibit Bacterial Membrane Function

Mechanism of Action	Drug Class	Specific Drugs	Spectrum of Activity	Clinical Use
Interacts with lipopolysaccharide in the outer membrane of gram-negative bacteria, killing the cell through the eventual disruption of the outer membrane and cytoplasmic membrane	Polymyxins	Polymyxin B	Narrow spectrum against gram-negative bacteria, including multidrug-resistant strains	Topical preparations to prevent infections in wounds
		Polymyxin E (colistin)	Narrow spectrum against gram-negative bacteria, including multidrug-resistant strains	Oral dosing to decontaminate bowels to prevent infections in immunocompromised patients or patients undergoing invasive surgery/procedures.
				Intravenous dosing to treat serious systemic infections caused by multidrug-resistant pathogens
Inserts into the cytoplasmic membrane of gram-positive bacteria, disrupting the membrane and killing the cell	Lipopeptide	Daptomycin	Narrow spectrum against gram-positive bacteria, including multidrug-resistant strains	Complicated skin and skin-structure infections and bacteremia caused by gram-positive pathogens, including MRSA

Query \(\PageIndex{1}\)

 

Inhibitors of Nucleic Acid Synthesis

Some antibacterial drugs work by inhibiting nucleic acid synthesis (Table \(\PageIndex{5}\)). For example, metronidazole is a semisynthetic member of the nitroimidazole family that is also an antiprotozoan. It interferes with DNA replication in target cells. The drug rifampin is a semisynthetic member of the rifamycin family and functions by blocking RNA polymerase activity in bacteria. The RNA polymerase enzymes in bacteria are structurally different from those in eukaryotes, providing for selective toxicity against bacterial cells. It is used for the treatment of a variety of infections, but its primary use, often in a cocktail with other antibacterial drugs, is against mycobacteria that cause tuberculosis. Despite the selectivity of its mechanism, rifampin can induce liver enzymes to increase metabolism of other drugs being administered (antagonism), leading to hepatotoxicity (liver toxicity) and negatively influencing the bioavailability and therapeutic effect of the companion drugs.

One member of the quinolone family, a group of synthetic antimicrobials, is nalidixic acid. It was discovered in 1962 as a byproduct during the synthesis of chloroquine, an antimalarial drug. Nalidixic acid selectively inhibits the activity of bacterial DNA gyrase, blocking DNA replication. Chemical modifications to the original quinolone backbone have resulted in the production of fluoroquinolones, like ciprofloxacin and levofloxacin, which also inhibit the activity of DNA gyrase. Ciprofloxacin and levofloxacin are effective against a broad spectrum of gram-positive or gram-negative bacteria, and are among the most commonly prescribed antibiotics used to treat a wide range of infections, including urinary tract infections, respiratory infections, abdominal infections, and skin infections. However, despite their selective toxicity against DNA gyrase, side effects associated with different fluoroquinolones include phototoxicity, neurotoxicity, cardiotoxicity, glucose metabolism dysfunction, and increased risk for tendon rupture.

Table \(\PageIndex{5}\): Drugs That Inhibit Bacterial Nucleic Acid Synthesis

Mechanisms of Action	Drug Class	Specific Drugs	Spectrum of activity	Clinical Use
Inhibits bacterial RNA polymerase activity and blocks transcription, killing the cell	Rifamycin	Rifampin	Narrow spectrum with activity against gram-positive and limited numbers of gram-negative bacteria. Also active against Mycobacterium tuberculosis.	Combination therapy for treatment of tuberculosis
Inhibits the activity of DNA gyrase and blocks DNA replication, killing the cell	Fluoroquinolones	Ciprofloxacin, ofloxacin, moxifloxacin	Broad spectrum against gram-positive and gram-negative bacteria	Wide variety of skin and systemic infections

Query \(\PageIndex{1}\)

 

Inhibitors of Metabolic Pathways

Some synthetic drugs control bacterial infections by functioning as antimetabolites, competitive inhibitors for bacterial metabolic enzymes (Table \(\PageIndex{6}\)). The sulfonamides (sulfa drugs) are the oldest synthetic antibacterial agents and are structural analogues of para-aminobenzoic acid (PABA), an early intermediate in folic acid synthesis (Figure \(\PageIndex{4}\)). By inhibiting the enzyme involved in the production of dihydrofolic acid, sulfonamides block bacterial biosynthesis of folic acid and, subsequently, pyrimidines and purines required for nucleic acid synthesis. This mechanism of action provides bacteriostatic inhibition of growth against a wide spectrum of gram-positive and gram-negative pathogens. Because humans obtain folic acid from food instead of synthesizing it intracellularly, sulfonamides are selectively toxic for bacteria. However, allergic reactions to sulfa drugs are common. The sulfones are structurally similar to sulfonamides but are not commonly used today except for the treatment of Hansen’s disease (leprosy).

Trimethoprim is a synthetic antimicrobial compound that serves as an antimetabolite within the same folic acid synthesis pathway as sulfonamides. However, trimethoprim is a structural analogue of dihydrofolic acid and inhibits a later step in the metabolic pathway (Figure \(\PageIndex{4}\)). Trimethoprim is used in combination with the sulfa drug sulfamethoxazole to treat urinary tract infections, ear infections, and bronchitis. As discussed, the combination of trimethoprim and sulfamethoxazole is an example of antibacterial synergy. When used alone, each antimetabolite only decreases production of folic acid to a level where bacteriostatic inhibition of growth occurs. However, when used in combination, inhibition of both steps in the metabolic pathway decreases folic acid synthesis to a level that is lethal to the bacterial cell. Because of the importance of folic acid during fetal development, sulfa drugs and trimethoprim use should be carefully considered during early pregnancy.

The drug isoniazid is an antimetabolite with specific toxicity for mycobacteria and has long been used in combination with rifampin or streptomycin in the treatment of tuberculosis. It is administered as a prodrug, requiring activation through the action of an intracellular bacterial peroxidase enzyme, forming isoniazid-nicotinamide adenine dinucleotide (NAD) and isoniazid-nicotinamide adenine dinucleotide phosphate (NADP), ultimately preventing the synthesis of mycolic acid, which is essential for mycobacterial cell walls. Possible side effects of isoniazid use include hepatotoxicity, neurotoxicity, and hematologic toxicity (anemia).

Figure \(\PageIndex{4}\): Sulfonamides and trimethoprim are examples of antimetabolites that interfere in the bacterial synthesis of folic acid by blocking purine and pyrimidine biosynthesis, thus inhibiting bacterial growth.

Table \(\PageIndex{6}\): Antimetabolite Drugs

Metabolic Pathway Target	Mechanism of Action	Drug Class	Specific Drugs	Spectrum of Activity
Folic acid synthesis	Inhibits the enzyme involved in production of dihydrofolic acid	Sulfonamides	Sulfamethoxazole	Broad spectrum against gram-positive and gram-negative bacteria
		Sulfones	Dapsone
	Inhibits the enzyme involved in the production of tetrahydrofolic acid	Not applicable	Trimethoprim	Broad spectrum against gram-positive and gram-negative bacteria
Mycolic acid synthesis	Interferes with the synthesis of mycolic acid	Not applicable	Isoniazid	Narrow spectrum against Mycobacterium spp., including M. tuberculosis

Query \(\PageIndex{1}\)

Query \(\PageIndex{1}\)

Query \(\PageIndex{1}\)

 

Inhibitor of ATP Synthase

Bedaquiline, representing the synthetic antibacterial class of compounds called the diarylquinolones, uses a novel mode of action that specifically inhibits mycobacterial growth. Although the specific mechanism has yet to be elucidated, this compound appears to interfere with the function of ATP synthases, perhaps by interfering with the use of the hydrogen ion gradient for ATP synthesis by oxidative phosphorylation, leading to reduced ATP production. Due to its side effects, including hepatotoxicity and potentially lethal heart arrhythmia, its use is reserved for serious, otherwise untreatable cases of tuberculosis.

Key Concepts and Summary

• Polymyxins are lipophilic polypeptide antibiotics that target the lipopolysaccharide component of gram-negative bacteria and ultimately disrupt the integrity of the outer and inner membranes of these bacteria.
• The nucleic acid synthesis inhibitors rifamycins and fluoroquinolones target bacterial RNA transcription and DNA replication, respectively.
• Some antibacterial drugs are antimetabolites, acting as competitive inhibitors for bacterial metabolic enzymes. Sulfonamides and trimethoprim are antimetabolites that interfere with bacterial folic acid synthesis. Isoniazid is an antimetabolite that interferes with mycolic acid synthesis in mycobacteria.