Mahmud's Portfolio - Antibacterial agents

Antibacterial agents

Learning objectives: Learn about antibacterial agents, their classification, chemistry, medicinal chemistry and structure activity relationship of antibacterial agents.

Antibacterial agents

Antibacterial Substances or antimicrobial chemotherapeutic agents are chemical substances used in the treatment of infectious diseases caused by pathogenic microorganisms. Their mode of action is to interfere with microbial metabolism; thereby producing a bacteriostatic or bacteriocidal effect on the microorganisms, without producing a like effect on the host cells.

Example:

Bacterial 30 s Ribosomal subunit inhibitors: Tetracyclines

Bacterial 50 s Ribosomal subunit inhibitors: Macrolides, Chloramphenicol, Erythromycins,

Bacterial cell wall inhibitors: Penicillins, Carbapenems, Cephalosporines

Folic Acid synthesis inhibitors: Sulfonilamides

Antibiotics are synthesized and secreted by some true bacteria, actinomycetes (Soil bacteria), and fungi. These molecules are designed in nature to inhibit or prevent the growth of other microorganisms in the environment. Today, antibiotics have been designed or modified based on this basic principle. There are other synthetic drugs produced through drug research that are capable of inhibiting bacterial growth.

Bacteriostatic Antibacterial Agents are the antibiotic agents which only inhibit (or retard) the growth and proliferation of bacteria, but do not kill them, rather the bacteria will destroy by their own toxin or by the completion of their certain life span, are called bacteriostatic Agents.

For example- The sulfonamides are primarily bacteriostatic, which means they slow or retard the multiplication of bacteria. This bacteriostatic activity is due to sulfonamide antagonism to para-aminobenzoic acid (PABA), a substance that some, but not all, bacteria need to multiply. Once the rate of bacterial multiplication is slowed, the defense mechanisms of the host (white blood cells) is able to rid the body of the invading microorganisms and therefore control the infection.

Bacteriocidal Antibacterial Agents are the antibiotic agents which can kill bacteria.

For example- Penicillins, Aminoglycosides.

Pathologic microorganism-Microorganisms in a certain amount that can produce diseases are called pathologic microorganism or pathogenic microorganism.

Anti-organism- Substances that are active against pathogenic microorganism are called anti-organism.

Causative microorganism- A specific microorganism which can causes a specific disease is called causative microorganism for that disease. For example-Salmonela typhi is the causative microorganism for typhoid, Mycobacterium Leprae for leprosy, Mycobacterium tubercoli for tuberculosis.

Predatorship- When one animal destroys another animal is called Predatorship. The tern Predatorship is confined in animal.

Antibiosis- When one living substance destroys another living substance (microorganism) then this is called antibiosis. The term “antibiosis” was first used by Charles Chamberland. This includes both plant and animal.

Antibiotics- Antibiotics are those substances which are derived from nonpathogenic microorganisms (bacteria, fungi, actinomycotes and also some non-pathogenic organism) and are used for either killing or inhibiting the growth of pathogenic microorganism without affecting the host tissues.

Antibiotics are specific chemical substances derived from or produced by living organisms that are capable of inhibiting the life processes of other organisms. The first antibiotics were isolated from microorganisms but some are now obtained from higher plants and animals. Over 3,000 antibiotics have been identified but only a few dozen are used in medicine. Antibiotics are the most widely prescribed class of drugs comprising 12% of the prescriptions in the United States.

For example-

I. Penicillin [Benzyl penicillin (Pen-G)] was first extracted from the mold/fungi Penicillium notatum.

II. Cephaiosporin in obtained from the mold/fungus Cephaiosporium acremonium.

III. Chloramphenicol- a synthetically manufactured broad-spectrum antibiotic initially isolated from the bacteria Streptomyces venezuelae in 1948 and was the first bulk produced synthetic antibiotic.

Antimicrobial drugs are used principally for the prophylaxis and treatment of bacterial infections.

Substitution on the Amino (NH2) group exerts variable effects on microorganisms. Bacteria synthesize benzoic acid (PABA) is a constitution of heterocyclic aromatic ring at 1-nitrogen with P.A.B.A. produce highly potent compound thus bacteria cannot synthesis Folic Acid and cannot multiply. Then they may killed by the action of sulfa drugs by their own metabolic toxicity.

[Remember:-Growth cycl (curve) of Bacteria. PELCZEAR:Microbiology]

Classification of Antimicrobial Agents

Several attempts were taken to classify the antibacterial agents. Among them, some most acceptable classifications are-

A. According to the type of killing to the bacteria, antibiotics can be classified as follows:

I. Bacteriocidal antibiotics: Kill bacteria

II. Bacteristatic antibiotics: Stop multiplication of bacteria: Macrolides are bacteriostatic for most bacteria.

B. According to the spectrum of activity:

I. Short spectrum or narrow-spectrum antibiotic: These target a specific type of bacterial infection and active against either gram positive cocci and bacilli or gram negative bacteria. For example- penicillin G, Streptomycin, Erythromycin, Cloxacillin.

II. Broad spectrum or wide-spectrum antibiotic: These are effective against a wide range of bacteria, fungi, protozoa, yeast etc. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of bacteria. For example- Ciprofloxacin, Amoxycillin, Ampicillin, Cephalosporin.

III. True broad spectrum antibiotic:: For example- Tetracycline.

C. According to the type of mechanism of action, antibacterial agents are classified as:

I. Inhibitors of cell wall synthesis:

Cell wall synthesis inhibitors generally inhibit some step in the synthesis of bacterial peptidoglycan-a protein that made up the bacterial cell wall. Inhibition of cell wall synthesis leads to bacterial cell wall lysis (brusting) and death. Generally they exert their selective toxicity against eubacteria because human cells lack cell walls. As animal cells do not have a cell wall, they remain unaffected by such agents. Agents operating in this way include Penicillin, Cephalosporins, Cycloserine, Bactracin.

II. Interferer or Inhibitor of intermediary cell metabolism:

Antibacterial agents which inhibit cell metabolism of bacteria are called antimetabolites. These compounds inhibit the metabolism of a microorganism, but not the metabolism of the host. They do this by inhibiting an enzyme-catalyzed reaction which is present in the bacterial cell but not in animal cells. They inhibit synthesis of purine and thymidylate precursors folic acid or tetrahydrofolate. The best known examples of antibacterial agents acting in this way are the Sulphonamides, PAS, Trimethoprim, etc.

III. Drugs that interact with the permiability of plasma membrane:

Some antibacterial agents bind and interact with the plasma membrane of the bacterial cells to affect membrane permeability (making it more permeable), cause leakage of cell membrane, this interferes the transport through membrane. The resulting water uptake leads to cell death. Polymixin, Tyrothricin, Colistin, Polyenes- Amphotercin-B, Nystatin operate in this way. These antibiotics are cationic, basic proteins that act like detergents (surfactants) and so often called detergent like antibiotics. They are bactericidal for gram-negative bacteria and have little to no effect on gram-positive since cell wall is too thick to permit access to membrane.

iv. Inhibitors or disruptors of protein synthesis:

Disruption of protein synthesis means that essential enzymes required for the survival of the cell can no longer be made. Agents which disrupt protein synthesis include the Aminoglycosides such as Erythromycin; tetracyclines, and chloramphenicol. etc.

v. Disrupters of nucleic acid synthesis or Inhibitors of nucleic acid transcription and replication:

Inhibition of nucleic acid function prevents cell division and/or, the synthesis of essen¬tial enzymes. The enzyme RNA polymerase synthesizes RNA according to a DNA template. The antibiotic rifampin interferes with prokaryotic RNA polymerase and thus, interferes with transcription. Fluoroquinolones inhibit DNA gyrase, a bacterial enzyme that unwinds DNA in preparation for replication and transcription. Both of these disruptions prevent bacteria from dividing to make more bacteria. Agents acting in this way include nalidixic acid and profalvin.

vi. Interferers with DNA synthesis: Example- Zodovudine, Idoxuridine.

vii. Interferers with DNA function: For example- Refampicin (Rifampin), Norfloxacin, Metronidazole.

viii. Cause misreading of m-RNA: For example- Aminoglycosides- Streptomycin, Neomycin etc.

Mnemonics to memorize classification of Antibiotic

1. Cell wall synthesis inhibitors Beat Bacterial Cell Cycle, Bust and vandalize fussy

Beta Lactum Antibiotics

Penicillins: Used for many gram-positive and select gram-negative bacteria (e.g., amoxicillin, penicillin G).

Cephalosporins: Divided into generations with increasing activity against gram-negative pathogens (e.g., cephalexin, ceftriaxone).

Carbapenems: Broad-spectrum agents typically reserved for severe or multi-drug resistant infections (e.g., meropenem, imipenem).

Monobactams: Narrow-spectrum agents active mainly against aerobic gram-negative bacteria (e.g., aztreonam)

Cyclosporine

Bacitracin

Vancomycin

Fosfomycin (a broad-spectrum, bactericidal, used primarily to treat uncomplicated urinary tract infections (UTIs) and bladder infections in women)

Mechanism of Action: It kills bacteria by irreversibly blocking an enzyme (MurA or phosphoenolpyruvate transferase) that bacteria need to build their cell walls. Structure: It is a phosphonic acid derivative structurally unrelated to other classes of antibiotics. It covers various Gram-positive and Gram-negative bacteria (such as E. coli and E. faecalis), making it useful against many multi-drug resistant strains.

How It Works

• Mechanism of Action: It kills bacteria by irreversibly blocking an enzyme (MurA or phosphoenolpyruvate transferase) that bacteria need to build their cell walls.

• Structure: It is a phosphonic acid derivative structurally unrelated to other classes of antibiotics.

• Activity: It covers various Gram-positive and Gram-negative bacteria (such as E. coli and E. faecalis), making it useful against many multi-drug resistant strains.

2. Protein Syntheris Inhibitors MALT protein

Macrolides

Aminoglycosides

Lincosamides

Tetracyclines

You are AT 30th street, but you want to "COM"e to 50th street

AT:

AMINOGLYCOSIDES

TETRACYCLINE

COM:

Chloramphenicol

Oxazolifinones

Macrolides: • Azithromycin (oral or parenteral)

• Clarithromycin (oral)

• Erythromycin (oral or parenteral; the prototype macrolide discovered in 1952)

• Fidaxomicin (oral, used specifically for Clostridioides difficile)

• Roxithromycin

FOlate Synthersis Inhibitors: SulFOnamides

Fluroquinolones [DNA has FOUR Nitrogenous bases!]

Mnemonics

Macrolides classification:

Mac throws CARES (macro=50s ribosomal subunit/protein synthesis inhibitors)

Clarithromycin

Arithromycin

Roxithromycin

Erythromycin

Spiramycin

Macrolides are the drug of choice for CLAW

Chancroid by hemophilus Corynebacterium, Camphylobacter

Legionella infection

Atypical Pneumonia

Wooping cough

Macrolides side effects:

Macrolides have MACRO side effect

Motility receptor stimulation>Tummy upset (diarrhea, abdominal pain)

Arrythmias/QT prolongation and allergy

Cholestasis and other liver problems like jaundice, elevated ALT/AST.

Rashes

Ototoxicity

Suprinfection (C. difficile)

Dapsone

Dapsone is a sulfone antibiotic (synthetic, sulfur-containing antibiotic) and anti-inflammatory medication available in oral and topical forms (diaminodiphenyl sulfone)—that stops bacterial and protozoal growth by blocking folic acid synthesis.

Primary Uses

• Leprosy (Hansen's disease): Used Usually given in combination with drugs like rifampicin and clofazimine in multi-drug therapy.

• Dermatitis herpetiformis: Dapsone is used to controls the itchy, blistered skin rash associated with gluten sensitivity in Dermatitis herpetiformis, a chronic, blistering skin condition associated with celiac disease.

• Acne and Skin Conditions: Oral and topical forms are prescribed or used off-label for inflammatory skin disorders like acne vulgaris, linear IgA bullous dermatosis, vasculitis, pyoderma gangrenosum and Sweet syndrome.

• Infection prophylaxis or to treat opportunistic Infections: Used as a second-line option to prevent and treat Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis in immunocompromised patients like people with weakened immune systems or HIV..

Mechanism of action

Dapsone or sulfones act similarly to sulfonamides (sulfa drugs) by competing with para-aminobenzoic acid (PABA) to inhibit the enzyme dihydropteroate synthetase, stopping folate production, thereby, blocking bacterial or fungal growth and folic acid synthesis. They also possess independent anti-inflammatory properties and provide strong anti-inflammatory effects that calm immune-mediated skin disorders.

Safety and Side Effects

• Blood disorders: Can cause hemolytic anemia or methemoglobinemia (reduced oxygen-carrying capacity in the blood). People with glucose-6-phosphate dehydrogenase (G6PD) deficiency face a much higher risk of severe anemia and must be screened beforehand. Regular blood tests are typically required.

• Allergies & Sensitivities: Dapsone and or sulfones are related to sulfa/sulfonamide chemistry, though some patients allergic to other sulfa drugs can tolerate dapsone under medical supervision. other side effects are Nausea, vomiting, headache, dizziness, insomnia, or mild skin irritation (for topical use).

• Precautions: To be avoided if the patient have a known allergy to sulfone or sulfonamide medications.

Dapsone hypersensitivity syndrome (DHS) or dapsone syndrome

Dapsone hypersensitivity syndrome (DHS), also known as dapsone syndrome—is a rare, potentially fatal drug reaction that resembles DRESS syndrome-drug rash with eosinophilia (an elevated count of eosinophils, a type of white blood cell) and systemic symptoms). It typically appears 1 week to 6 months (most commonly 5 to 6 weeks) after starting dapsone therapy, which is often used to treat leprosy, dermatitis herpetiformis, or severe acne.

Major warning sign/Classic Clinical Triad and Manifestations

The syndrome is defined by a primary triad and multi-organ involvement:

• Fever: High-grade fever and flu-like symptoms.

• Skin Rash: Widespread maculopapular eruption, exfoliative dermatitis, or erythema multiforme-like lesions.

• Internal Organ Involvement: Most commonly hepatitis (elevated liver enzymes, jaundice, hepatomegaly), along with lymphadenopathy, hemolytic anemia, eosinophilia, or renal/pulmonary complications.

• Hemolytic anemia: Hemolytic anemia is a well-known and recognized side effect of oral dapsone. Dapsone breaks down into a metabolite (dapsone hydroxylamine) that causes oxidative damage to red blood cells. This damage causes hemoglobin to clump into structures called Heinz bodies, which lead to the premature destruction (hemolysis) of red blood cells by the spleen. Mild-to-moderate hemolysis can happen even at normal therapeutic doses (50 to 100 mg per day), while more severe hemolytic anemia is more likely at higher doses (greater than 200 mg per day). People with a genetic condition called glucose-6-phosphate dehydrogenase (G6PD) deficiency are at a much higher risk for severe, life-threatening hemolytic anemia when taking dapsone. However, dapsone can still cause hemolysis in patients with normal G6PD levels.

Common Symptoms of Hemolytic anemia

• Fatigue, weakness, or lethargy

• Pale skin or nail beds (pallor)

• Shortness of breath

• Jaundice (yellowing of the skin or eyes) or dark urine in more prominent cases

Antidote of dapsone toxicity

The primary antidote for dapsone toxicity (which causes methemoglobinemia) is methylene blue, with ascorbic acid (vitamin C) used as an alternative or backup.

Key Antidotes and Treatments

• Methylene Blue:

• Acts as the primary effective antidote for symptomatic methemoglobinemia (typically when levels are >20% to 30% or when tissue hypoxia/cyanosis is present).

• Standard initial dose is usually 1 to 2 mg/kg administered intravenously over 5 minutes, which can be repeated if symptoms persist. Continuous infusion may be needed because dapsone has a long half-life and can cause rebound methemoglobinemia 4 to 12 hours later.

• Warning: Methylene blue is generally contraindicated in patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency, as it can trigger severe hemolysis in these individuals.

• Ascorbic Acid (Vitamin C):

• Used as an alternative reducing agent when methylene blue is unavailable or contraindicated (such as in G6PD deficiency). It works more slowly than methylene blue.

• Multiple-Dose Activated Charcoal (MDAC):

• Not a direct chemical antidote, but crucial for management. Repeated doses interrupt the enterohepatic circulation of dapsone and accelerate its elimination from the body.

• Supportive Care:

• Supplemental oxygen and monitoring for hemolytic anemia are standard parts of emergency treatment.

Key Causes and Risk Factors

• Trigger: Caused by an idiosyncratic (unpredictable/allergic) immune-mediated reaction to dapsone metabolites rather than a simple overdose.

• Genetics: Strongly linked to the HLA-B*13:01 genetic allele, which is a major risk factor—particularly in Asian populations.

Management and Treatment

• Immediate Drug Discontinuation: Dapsone must be stopped right away.

• Supportive Care: Intensive monitoring and organ support in a clinical setting.

• Systemic Corticosteroids: Oral or intravenous glucocorticoids (such as prednisolone) are typically administered with a slow taper over several weeks.

• Prognosis: If unrecognized or untreated, mortality rates can reach roughly 10% to 23% due to liver failure or multi-organ damage. Late-onset hypothyroidism is a known long-term complication that requires follow-up screening.