Lesson 16

Question 1

What is antibacterial chemotherapy?

Answer 1

In the realm of medical treatment, antibacterial chemotherapy encompasses a broad spectrum of agents designed to combat bacterial infections. These agents can be delineated into two primary categories: antibacterials and antibiotics. Each type plays a crucial role in managing bacterial diseases and has distinct characteristics in terms of origin, mechanism of action, and effectiveness.

Antibacterials consist of both naturally occurring and synthetic compounds. Their primary purpose is to inhibit the growth of or to kill bacteria, thus aiding in the treatment of bacterial infections.

Natural antibacterials are produced by various organisms as a means of defense against bacterial pathogens. Over time, humans have harnessed and refined these substances for therapeutic use.

In contrast to their natural counterparts, synthetic antibacterials are the result of humans. They are designed, engineered, and produced to target specific bacterial functions or structures. An example of such a synthetic compound is ciprofloxacin, which belongs to the class of quinolones.

Antibiotics are a subset of antibacterials with a natural origin. Penicillin, one of the most renowned antibiotics, was originally derived from the Penicillium mold. Through the process of deep fermentation, scientists were able to optimize the production of penicillin, leading to its widespread therapeutic use. While penicillin was a groundbreaking discovery, the emergence of resistant bacteria has greatly reduced its effectiveness as a standalone treatment. However, through industrial modifications, penicillin has been chemically altered to produce a variety of penicillin derivatives, collectively known as penicillins.

Antibacterial agents exert their effects by targeting specific bacterial cell processes that are essential for bacterial survival and proliferation. The primary targets are:

1. Synthesis of the Cell Wall: The cell wall is critical for bacterial integrity and survival. Antibacterial drugs such as penicillins, cephalosporins, and carbapenems interfere with cell wall synthesis. Collectively, these drugs are known as beta-lactam antibiotics due to their shared beta-lactam ring structure, which is key to their mechanism of action.
2. DNA Replication and Transcription: The ability of bacteria to replicate and express their genetic material is fundamental to their growth. Fluoroquinolones are a class of drugs that target bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication and transcription.
3. Protein Synthesis: Bacteria require proteins for various cellular functions, including metabolism and cell structure. Antibacterial drugs such as macrolides, aminoglycosides, and tetracyclines disrupt bacterial protein synthesis by interacting with the bacterial ribosome, thereby inhibiting the translation of genetic information into functional proteins.

Question 1

Speak about beta lactam antibiotics

Answer 1

BETA-LACTAM ANTIBIOTICS

Beta-lactam antibiotics represent a class of antibacterial agents that are among the most widely used in the treatment of bacterial infections. These compounds are characterized by the presence of a beta-lactam ring, a four-membered lactam structure (a cyclic amide) that is crucial for their antibacterial activity. The beta-lactam ring is highly reactive due to the strain on the amide bond, which is pivotal for the antibiotic’s mechanism of action. The beta-lactam ring itself is a cyclic hydrocarbon which features a strained ring. It comprises an alpha carbon connected to a carbonyl group and a beta carbon, where the substitution occurs to give rise to the different classes of beta-lactam antibiotics. The reactivity of the beta-lactam ring is essential for the inhibition of bacterial cell wall synthesis, but it also renders the molecule susceptible to hydrolysis by bacterial enzymes known as beta-lactamases.

We have many kinds of beta lactam antibiotics:

• Penicillins are perhaps the most well-known group within the beta-lactam antibiotics. They are characterized by a thiazolidine ring attached to the beta-lactam structure. Many penicillins are suitable for oral administration. Augmentin, a combination of amoxicillin (a penicillin derivative) and clavulanic acid (a beta-lactamase inhibitor), is a commonly used form of penicillin.
• Cephalosporins are another major class of beta-lactam antibiotics, and they typically have a dihydrothiazine ring linked to the beta-lactam. These antibiotics are often used in hospital settings due to their parenteral routes of administration and spectrum of activity.
• Carbapenems are a relatively newer class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They are administered intravenously in hospital settings to manage severe infections and to attempt to curb the development of antibiotic resistance.
• Monobactams, with aztreonam as a prime example, are composed solely of the beta-lactam ring without additional cyclic structures. They are used intravenously for their effective coverage against Gram-negative bacteria.

The bacterial cell wall is a complex structure composed of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) linked by short peptide chains. In Gram-positive bacteria, a pentaglycine bridge facilitates the cross-linking, while in Gram-negative bacteria, direct cross-linking occurs between the amino acids of adjacent strands.

Beta-lactam antibiotics target the bacterial cell wall, specifically the enzymes involved in the cross-linking of peptidoglycan layers. The primary target enzyme is the transpeptidase, which catalyzes the formation of peptide cross-links between adjacent glycan strands. Beta-lactam antibiotics mimic the D-Ala-D-Ala moiety of the peptidoglycan precursor, allowing them to bind to the active site of the transpeptidase and irreversibly inhibit its activity, leading to the disruption of cell wall synthesis.

Beta-lactam antibiotics possess a broad spectrum of activity, effective against a wide range of Gram-positive and Gram-negative bacteria. Their efficacy, however, can be impacted by the presence of beta-lactamase-producing bacteria, which necessitates the use of combination therapies or the development of beta-lactamase-resistant variants.

Bacterial resistance to beta-lactam antibiotics is primarily mediated by the production of beta-lactamases, enzymes that hydrolyze the beta-lactam ring, rendering the antibiotic ineffective. The combination of amoxicillin with clavulanic acid in Augmentin serves to protect amoxicillin from degradation by beta-lactamases, thereby extending its spectrum of activity. Bacterial resistance can be propagated both vertically, from parent to progeny, and horizontally, among bacteria within a community. This can occur through spontaneous mutations or horizontal gene transfer mechanisms such as conjugation, transduction, or transformation.

SAR (structure-activity relationship) is the study of the relationship between the chemical structure of beta-lactam antibiotics and their pharmacological activity, it is critical in the development of newer, more effective agents. Modifications to the beta-lactam ring and its side chains can result in compounds with enhanced stability, spectrum, and resistance to bacterial defense mechanisms.

Question 2

Speak about what are fluoroquinolones, and what are their possible chemical modifications

Answer 2

luoroquinolones represent a class of synthetic antibacterial agents, distinguished from traditional antibiotics by their complete synthetic origins. These potent broad-spectrum drugs are used to treat a variety of infections and are available in multiple forms: oral capsules, intravenous solutions, ophthalmic drops, and topical creams. The most commonly recognized fluoroquinolone is ciprofloxacin. However, the rise of drug resistance is a growing concern in the clinical use of these agents.

The chemical backbone of fluoroquinolones is the bicyclic aromatic molecule quinoline. The introduction of a carbonyl group to quinoline disrupts its aromaticity, creating quinolones. Early quinolones, such as nalidixic acid, served as the foundation for the development of modern fluoroquinolones. The key structural enhancement in modern fluoroquinolones is the addition of a fluorine atom, which significantly augments both their potency and antibacterial activity.

Exploring the structure-activity relationship (SAR) of fluoroquinolones reveals that various substitutions on the quinolone skeleton can increase the spectrum and potency of the drug:

• Position 1: These modifications enhance bioavailability and the volume of distribution. May lead to genetic toxicity, causing DNA damage.
• Position 5: The placement of a methyl group improves the activity against Gram-positive bacteria but also contributes to increased toxicity. Modifications in this position increase lipophilicity, which can impact both activity and toxicity, it is associated with genotoxicity, phototoxicity, and cardiotoxicity.
• Position 6: The addition of a fluoride increases the drug’s potency by enhancing its ability to inhibit bacterial topoisomerases. It improves tissue penetration and distribution.
• Position 7: A bulky group in this position can extend the half-life and enhance CNS penetration, beneficial for treating central nervous system infections.
• Position 8: Alters bioavailability and half-life, impacting both efficacy and toxicity profiles. Can contribute to phototoxicity.

Through the years, the quinolone structure has been modified, resulting in four generations of drugs, each with increased activity and a broader spectrum of action. However, these modifications have also been associated with increased toxicity. In animal studies, fluoroquinolones have been known to provoke seizures, linked to their interaction with GABA receptors. So, despite their effectiveness, fluoroquinolones are associated with a range of toxicities:

• Tendonitis and Tendon Rupture: Notably with levo floxacin after prolonged use.
• Cardiotoxicity: Includes the risk of ventricular arrhythmias such as torsade de pointes.
• Phototoxic Dermatitis: Ranging from mild to bullous reactions, exacerbated by exposure to sunlight.
• CNS Effects: Including seizures, particularly with drugs that penetrate the CNS effectively.

Question 3

What is the mechanism of action of fluoroquinoles, what are the difference generations? speak also about the bacterial resistance

Answer 3

The first generation of fluoroquinolones is represented by nialidixic acid. Identified during a research study on malaria, nalidixic acid is a simple quinolone still available today but is largely overshadowed by more advanced fluoroquinolones.

Later Generations include Norfloxacin, Ciprofloxacin, Levofloxacin, Moxifloxacin, and Grebafloxacin. Each subsequent generation of fluoroquinolones brought improvements in bioavailability, spectrum, and half-life, as well as specific enhancements in activity against different bacterial groups. However, these benefits were often accompanied by increased risks of toxicity.

For example, grepafloxacin was removed from the market due to its association with severe cardiotoxic effects, notably ventricular tacharrhythmia.

Fluoroquinolones exert their antibacterial effects by interfering with bacterial DNA replication and repair. They target topoisomerase II (also known as DNA gyrase) and topoisomerase IV, enzymes that are essential for DNA replication. By inhibiting these enzymes, fluoroquinolones prevent the unwinding of DNA that is necessary for replication and transcription, ultimately leading to bacterial cell death.

Bacterial resistance to fluoroquinolones is often due to mutations in the genes encoding DNA gyrase and topoisomerase IV. These mutations reduce the drugs’ ability to bind to and inhibit the enzymes, rendering them less effective.

In conclusion, fluoroquinolones have been a significant advancement in the treatment of bacterial infections due to their broad-spectrum activity and potent action. However, the development of bacterial resistance and the potential for significant adverse effects necessitate careful prescription and monitoring by healthcare professionals. Ongoing research into the SAR of fluoroquinolones is essential to develop safer and more effective drugs to combat bacterial resistance while minimizing toxicity.