Systems Pharmacology: Cell Wall Synthesis Inhibitors - Penicillins PDF

Systems Pharmacology & Chemotherapeutics SCPCB3-44 WEEK 1: ANTIBIOTICS - CELL WALL SYNTHESIS INHIBITORS PENICILLINS The e:ectiveness of an antibacterial agent is influenced by its ability to cross bacterial cell walls...

Systems Pharmacology & Chemotherapeutics SCPCB3-44 WEEK 1: ANTIBIOTICS - CELL WALL SYNTHESIS INHIBITORS PENICILLINS The e:ectiveness of an antibacterial agent is influenced by its ability to cross bacterial cell walls, primarily the peptidoglycan layer. The drug must pass these barriers to reach its targets, such as penicillin-binding proteins (PBPs), enzymes responsible for the synthesis and maintenance of bacterial cell walls. GRAM-POSTITIVE VS GRAM-NEGATIVE BACTERIA Bacterial Type Peptidoglycan Layer Outer Membrane Penicillin’s ELectiveness Gram-Positive Thick (lots) No Highly e:ective; can easily reach penicillin-binding proteins Gram -Negative Thin (not lots) Yes Less e:ective; requires porin (Lipopolysaccharide) channels to reach penicillin- binding proteins KEY PHYSIOCHEMICAN PROPERTIES INFLUENCING DRUG PENETRATION Property ELect on Drug Impact on Gram + Impact on Gram – bacteria Penetration bacteria Size Smaller drugs Easy penetration of Harder to penetrate due to penetrate more thick peptidoglycan outer membrane easily layer Charge Influences Minimal impact Charged drugs may struggle interaction with with the LPS barrier bacterial membranes Hydrophobicity Hydrophobic drugs Easy penetration (no Hydrophilic drugs require cross lipid outer membrane) porin channels for membranes; penetration hydrophilic need porins  Systems Pharmacology & Chemotherapeutics SCPCB3-44 Penicillin's Mechanism of Action Penicillins, a type of β-lactam antibiotics, target PBPs located in the periplasmic space. By inhibiting PBPs, penicillins prevent the cross-linking of peptidoglycan, disrupting the bacterial cell wall and leading to cell lysis. Gram-Positive Bacteria: The thick but porous peptidoglycan layer allows penicillins to easily reach PBPs and disrupt cell wall synthesis. Gram-Negative Bacteria: Penicillins must first cross the LPS outer membrane via porin channels to access PBPs, making them less e:ective. Changes in porins or e:lux pumps can reduce drug uptake. Water Solubility of Penicillins (Hydrophilicity) Penicillins are hydrophilic, making it di:icult for them to cross lipid-rich outer membranes of Gram- negative bacteria without the help of porin channels. Crossing the Lipopolysaccharide (LPS) Barrier in Gram-Negative Bacteria The LPS membrane in Gram-negative bacteria prevents easy entry of hydrophilic molecules. Porin channels allow passage of small, hydrophilic drugs like penicillin into the periplasmic space, where PBPs are located. Limitations: Bacteria can modify porins or develop e:lux pumps to expel the drug, reducing its e:icacy. ANTIBACTERIAL SPECTRUM OF PENICILLINS The antimicrobial spectrum of an antibiotic defines the range of bacteria it can e:ectively target. Penicillins can be categorized based on their spectrum of activity and origin. Type ELective Examples Advantages Disadvantages Against Broad-Spectrum Both Gram- Tetracyclines, Treats Risk of resistance, disrupts positive & Carbapenems, unknown/mixed normal flora Gram-negative Amoxicillin- infections Clavulanate, Fluoroquinolones Narrow-Spectrum Specific group Penicillin G, Lower Ine:ective for mixed (either Gram- Vancomycin, resistance risk, infections, requires pathogen positive or Isoniazid preserves ID Gram-negative) normal flora NATURAL VS. SYNTHETIC ANTIBIOTICS Type Description Examples Advantages Disadvantages Natural Antibiotics Derived from Penicillin, Potent against certain Complex structures, microorganisms Streptomycin, bacteria evolved to susceptible to natural (bacteria, fungi) Tetracycline combat microbes resistance mechanisms Synthetic Manufactured Sulphonamides, Tailored e:icacy, stable, High development costs, Antibiotics entirely in Fluoroquinolones, mass-producible potential for rapid laboratories Linezolid resistance development using chemical processes Semi-synthetic Hybrid of Amoxicillin, Enhanced May still face resistance Antibiotics natural and Cefuroxime activity/pharmacological issues similar to natural synthetic properties, such as antibiotics antibiotics; improved bioavailability derived from or resistance natural sources with chemical modifications  Systems Pharmacology & Chemotherapeutics SCPCB3-44 PHARMACOKINETICS OF PENICILLINS Penicillins' e:ectiveness is influenced by their stability to stomach acid and susceptibility to β- lactamases. Stability to stomach acid: important for oral administration because a drug must survive the acidic conditions to be absorbed into the bloodstream and exert its therapeutic e:ect β-lactamases: bacterial enzymes that hydrolyse the β-lactam ring of antibiotics which inactivates the antibiotic, allowing bacteria to resist treatment STABILITY OF STOMACH ACID Examples Characteristics Advantages Disadvantages Uses Acid-Stable Amoxicillin, - Resistant to - Oral None - Suitable for outpatient Penicillins Penicillin V stomach acid administration is treatment where oral degradation. convenient intake is preferred. - Structural modifications protect the β- lactam ring. Acid-Labile Penicillin G - Rapidly degraded - E:ective when - Cannot be - Used in severe Penicillins by stomach acid. administered via taken orally. infections where oral non-oral routes. administration is not feasible (IV or IM required). SUSCEPTIBILITY TO β-LACTAMASES many natural penicillin’s (penicillin G & V) are highly susceptible to β-lactamases produced by resistant bacteria these enzymes cleave the β-lactam ring, making the antibiotic ine:ective against the bacteria bacteria can produce various types of β-lactamases, some of which are highly specific to certain antibiotics (penicillinases), while others (such as extended-spectrum β-lactamases, or ESBLs) can degrade a wide range of β-lactam antibiotics. Examples Characteristics Advantages Uses Penicillinase- Methicillin, - Structural - E:ective - Used in infections caused by β- Resistant Penicillin’s Oxacillin, modifications (at R- against β- lactamase-producing bacteria Nafcillin, side chain) that lactamase- (e.g., Staphylococcus aureus, Dicloxacillin prevent β-lactamase producing excluding MRSA). access to the β- bacteria. lactam ring. β-lactamase Clavulanic - Inhibit β-lactamase - Extends the - Combined with penicillins (e.g., Inhibitors acid, enzymes, protecting spectrum of Amoxicillin-Clavulanate) to Sulbactam, antibiotics from penicillins. combat β-lactamase-producing Tazobactam degradation. bacteria.  Systems Pharmacology & Chemotherapeutics SCPCB3-44 PHARMACOKINETICS & SAFETY OF PENICILLINS Penicillin’s are widely used due to their broad activity and relatively low toxicity. However, they can cause various side e:ects, with hypersensitivity being the most significant concern. Cross-reactivity: Patients with a known allergy to penicillin may also show cross-reactivityto other β- lactam antibiotics, such as cephalosporins, because they share a similar β-lactam structure. However, this cross-reactivity is less common with newer-generation cephalosporins. Adverse ELect Description Examples/Symptoms Hypersensitivity (Allergy) Immune-mediated reactions Mild: Rash, itching ranging from mild to severe Moderate: urticaria (hives) (anaphylaxis) Severe: anaphylactic shock (di:iculty breathing, swelling, drop in BP, rapid Cross reactivity with other pulse, dizziness) β-lactams may occur Treatment: immediate medical intervention, often with epinephrine, antihistamines, and corticosteroids. GI ELects Nausea, vomiting, Rash, itching, urticaria, anaphylactic diarrhea, C. di&icile colitis shock Neurological ELects Central nervous system Seizures, confusion (in high doses or disturbances patients with kidney impairment) Haematological ELects Blood cell abnormalities Eosinophilia, hemolytic anemia, leukopenia Renal ELects Kidney inflammation Interstitial nephritis (rare) Hepatic ELects Liver dysfunction Elevated liver enzymes, jaundice, hepatitis (rare)  Systems Pharmacology & Chemotherapeutics SCPCB3-44 WEEK 1: ANTIBIOTICS – PROTEIN SYNTHESIS INHIBITORS PROTEIN SYNTHESIS mRNA template, ribosomes, tRNAs, and enzymatic factors are NB. The small ribosomal subunit forms on the mRNA template at the Shine-Dalgarno sequence (prokaryotes) or the 5′ cap (eukaryotes). Translation begins at the initiating AUG on the mRNA, specifying methionine. The formation of peptide bonds occurs between sequential amino acids specified by the mRNA template according to the genetic code. Charged tRNAs enter the ribosomal A site, and their amino acid bonds with the amino acid at the P site. The entire mRNA is translated in three-nucleotide “steps” of the ribosome. When a nonsense codon is encountered, a release factor binds and dissociates the components and frees the new protein. Folding of the protein occurs during and after translation. PROTEIN SYNTHESIS INHIBITORS Antibiotic Class Mechanism of Uses Pharmacokinetics ELects & Antimicrobial Action Actions Spectrum Tetracyclines Bind to 30S Respiratory - A: Reduced by - Bacteriostatic. Broad- (e.g. Tetracycline, ribosomal infections, STIs food, dairy, - SE: GI distress, spectrum: Doxycycine, subunit, (chlamydia, antacids due to photosensitivity, E:ective Minocycline) preventing syphilis), chelation. teeth against Gram- aminoacyl- Rickettsial - D: Well discoloration (in positive, tRNA from infections, distributed, except children), Gram-negative attaching to Acne vulgaris, in CSF. hepatotoxicity, bacteria, mRNA- Malaria - M: urine (except nephrotoxicity. atypical ribosome prophylaxis Doxycycline & bacteria complex (Doxycycline), Minocycline, which (Mycoplasma, (bacteriostatic) Lyme disease. are excreted via Chlamydia), liver). rickettsiae, - HL: 6-20 hrs spirochetes, (Doxycycline has protozoa. longer half-life). Glycylcyclines (e.g. Bind to 30S Complicated - A: IV Bacteriostatic. Broad- Tigecycline) ribosomal skin/soft tissue administration - SE: Nausea, spectrum: subunit, infections, (poor oral vomiting, E:ective overcoming intra- bioavailability). increased risk of against Gram- resistance in abdominal - D: Extensive death in severe positive tetracycline- infections, tissue distribution; infections (MRSA, VRE), resistant community- low blood levels. (sepsis). Gram-negative bacteria acquired - M: Liver; excreted bacteria, (bacteriostatic) pneumonia, via biliary and renal anaerobes. drug-resistant routes. Lacks activity pathogens - HL: 36 hours. against (MRSA, VRE). Pseudomonas, Proteus.  Systems Pharmacology & Chemotherapeutics SCPCB3-44 Antibiotic Class Mechanism Uses Pharmacokineti ELects & Antimicrobia of Action cs Actions l Spectrum Aminoglycosides (e. Bind to 30S Serious Gram- - A: IV or IM (poor - Bactericidal. Primarily g. Gentamicin, ribosomal negative oral absorption). - SE: Gram- Amikacin, subunit, infections (e.g. - D: Extracellular Ototoxicity, negative Tobramycin) causing Pseudomonas) fluid, low CSF nephrotoxicit aerobes (e.g. misreading of , sepsis, penetration. y, Pseudomona mRNA endocarditis - M: Not neuromuscul s, E. coli, (bactericidal). (combined metabolized, ar blockade Klebsiella), with β- excreted by (high doses). limited Gram- lactams), TB kidneys. positive (second-line). - HL: 2-3 hours (synergy with (adjust dosing β-lactams). based on renal function). Macrolides (e.g. Bind to 50S Respiratory - A: Well - E:ective Erythromycin, ribosomal infections, absorbed orally bacteriostatic against Clarithromycin, subunit, atypical - D: Good tissue / Gram-+ Azithromycin) inhibiting infections penetration, poor Bactericidal cocci, nascent (Mycoplasma, CSF. SE: GI upset, atypical peptide exit Chlamydia, - M: Liver QT bacteria tunnel Legionella), (CYP450 prolongation, (Mycoplasma (bacteriostati STIs enzymes). cholestatic , Chlamydia), c, (Chlamydia, - HL: hepatitis Legionella, bactericidal Gonorrhoea), Azithromycin (40- some Gram- at higher H. pylori 68 hrs), negative doses). eradication Clarithromycin bacteria (peptic ulcer (3-7 hrs). (Haemophilu disease). s influenzae). Clindamycin Bind to 50S Anaerobic - A: Well - E:ective ribosomal infections absorbed orally. bacteriostatic against subunit, (Bacteroides), - D: Penetrates SE: Diarrhea Gram-+ inhibiting skin/soft tissue tissues, including (risk of C. cocci protein infections bone, but not di:icile (MRSA), synthesis (MRSA), CSF. infection), anaerobes (bacteriostati osteomyelitis, - M: Liver; rash, (Bacteroides c) dental excreted in bile hepatotoxicity ). Ine:ective infections. and urine.. against - HL: 2-3 hours. Gram-neg aerobes. Chloramphenicol Bind to 50S Typhoid fever, - A: Well - Broad- ribosomal bacterial absorbed orally. Bacteriostatic spectrum: subunit, meningitis -D: Wide, / Bactericidal Gram- inhibiting (limited including CSF. at high doses positive, peptide bond resource - M: Liver; - SE: Bone Gram- formation settings), excreted in urine. marrow negative, (bacteriostati Rickettsial - HL: 1.5-3.5 suppression, anaerobic c, infections hours. aplastic bacteria, bactericidal (Rocky anaemia, grey Rickettsia, in high Mountain baby Chlamydia. doses). spotted fever if syndrome tetracyclines (neonates), GI contraindicate upset. d)  Systems Pharmacology & Chemotherapeutics SCPCB3-44 WEEK 1: ANTIBIOTICS – FOLATE SYNTHESIS INHIBITORS Folate: essential vitamin People likely to su:er from folic acid deficiency: o Pregnant women → advised to take folic acid supplements as deficiency can cause Spina bifida (congenital abnormality – neural tube defect) o Alcoholics 2 important forms of folic acid: methyltetrahydrofolate & methylene tetrahydrofolate FOLATE ANTAGONISTS Antibiotic Class Mechanism of Uses Pharmacokinetics ELects & Antimicrobial Action Actions Spectrum Folate Inhibit folate Urinary tract - A: Well absorbed - Broad- Antagonists (e.g. synthesis, infections, respiratory orally. Bactericidal. spectrum: Trimethoprim- essential for infections (e.g. - D: Good tissue - SE: Allergic E:ective Sulfamethoxazole) bacterial DNA pneumonia in penetration, reactions, against many synthesis. immunocompromised including CSF. skin rashes, Gram-positive Sulfamethoxazole patients), GI - M: Metabolised in GI upset, (e.g. inhibits infections (Shigella, the liver; excreted bone Streptococcus dihydropteroate Salmonella), PCP in urine. marrow pneumoniae) synthase; prophylaxis in HIV - HL: 8-10 hours. suppression and Gram- trimethoprim patients. (with long- negative inhibits term use). bacteria (e.g. dihydrofolate E. coli, reductase. Haemophilus Together, they influenzae). block folate synthesis (bactericidal).  Systems Pharmacology & Chemotherapeutics SCPCB3-44 WEEK 1: ANTIBIOTICS – FOLATE SYNTHESIS INHIBITORS Antibiotic Class Mechanism of Uses Pharmacokinetics ELects & Antimicrobial Action Actions Spectrum Fluoroquinolones Inhibit bacterial UTIs, - A: Well absorbed - Bactericidal. Broad-spectrum: (e.g. Ciprofloxacin, DNA synthesis respiratory orally; impaired by - SE: GI E:ective against Levofloxacin, by targeting DNA infections, GI divalent/trivalent disturbances, Gram-negative (e.g. E. Moxifloxacin) gyrase and infections (e.g. cations. dizziness, coli, Pseudomonas topoisomerase Salmonella), - D: Widely tendon rupture, aeruginosa) and some IV, leading to bone/joint distributed (lungs, QT prolongation, Gram-positive bacteria bacterial death infections, prostate, bone). risk of C. (e.g. Staphylococcus (bactericidal). skin/soft tissue - M: Eliminated in diLicile. aureus). infections, urine; some hepatic anthrax metabolism. prophylaxis - HL: 4-12 hours. (Ciprofloxacin). Sulphonamides Inhibit UTIs, burns - A: Well absorbed - Bacteriostatic. E:ective against (e.g. dihydropteroate (topical), orally. - SE: Allergic Gram-positive Sulfamethoxazole, synthase, toxoplasmosis, - D: Widely reactions, Steve (e.g. Staphylococcus Sulfadiazine) blocking folate rheumatic distributed, ns-Johnson aureus) and some and DNA fever including CNS. syndrome, GI Gram-negative synthesis prophylaxis (in - M: Hepatically disturbances, bacteria (e.g. E. coli). (bacteriostatic). penicillin- metabolised; renal renal toxicity. allergic excretion. patients). - HL: 6-12 hours. Trimethoprim Selectively Used with - A: Well absorbed - Bactericidal E:ective against inhibits sulfamethoxaz orally. (with Gram-positive dihydrofolate ole (TMP-SMX) - D: Widely sulphonamides). (e.g. Streptococcus reductase, for UTIs, distributed, - SE: GI upset, pneumoniae) and blocking folate respiratory including CNS. skin rashes, Gram-negative (e.g. E. synthesis infections, PCP - M: Liver hyperkalaemia. coli, Klebsiella) (bactericidal prophylaxis, metabolism; bacteria. when combined bacterial excreted in urine. with prostatitis. - HL: 8-11 hours. sulphonamides). Urinary Tract - Nitrofurantoin: Uncomplicated Nitrofurantoin: Nitrofurantoin: Nitrofurantoin: Antiseptics (e.g. Inhibits bacterial UTIs. -A: Well absorbed - Bactericidal in E:ective against Nitrofurantoin, enzymes and orally. urine. Gram-positive Methenamine) disrupts cell wall - D: Concentrates in - SE: Nausea, (e.g. Staphylococcus synthesis urine. vomiting, saprophyticus) and (bactericidal). - M: Minimal pulmonary Gram-negative (e.g. E. hepatic toxicity coli) bacteria in urine. metabolism; (prolonged use). excreted in urine. - HL: 1 hour. - Methenamine: Methenamine: Methenamine: Methenamine: Hydrolyses in - A: Well absorbed - Bactericidal in E:ective against acidic urine to orally. acidic urine. Gram-negative and form - D: Excreted in - SE: Rare GI Gram-positive bacteria formaldehyde urine. upset, allergic in urine. (antimicrobial - Requires acidic reactions. e:ect). urine for activation. - HL: Variable.