Antibacterial drugs

There are 4 major targets of bacterial antibiotics which are commonly used. Antibiotics are either bactericidal (directly kill bacteria) or bacteriostatic (inhibit cell growth).

 

a) Target Cell Wall

The cell wall is very important in bacteria as it is needed to withstand turgor pressure.

– It is made from peptidoglycan which is much thicker in Gram +ve bacteria.

The cell wall is made from a cell wall pentapeptide precursor, which is added to a peptidoglycan chain.

– This then undergoes crosslinking to link together the peptide strands making the cell wall strong

– This uses an enzyme called transpeptidase which first binds to the precursor by its D-Ala-D-Ala end

 

Many antibiotics interfere with this transpeptidase enzyme, preventing synthesis of the cell wall:

a) Beta-lactam antibiotics

  • Penicillins

These have a beta-lactam ring which looks similar to the terminal D-Ala-D-Ala

– They irreversibly bind the bacterial transpeptidase and prevent cross-linking of the peptidoglycan strands

– They are bactericidal and Gram +ve bacteria are particularly susceptible due to their thick cell wall

 

  • Penicillin G – early penicillin which only treats Gram +ve bacteria
  • Flucloxacillin – Penicillin-type antibiotic which is used mainly against Staphylococcus Aureus
  • Ampicillin + Amoxicillin – extended spectrum which treat both Gram +ve and –ve bacteria

 

Side effects: Hypersensitivity reaction (rash, GI upset, Steven’s Johnson syndrome) seen in 10%

– Amoxicillin –> gives a rash with infectious mononucleosis

– Flucloxacillin + Co-Amoxiclav –> can give cholestasis

 

One problem is that bacteria produce the enzyme Beta-lactamase which inactivates the antibiotic.

– To overcome this, these antibiotics are often co-administered which B-lactamase inhibitors:

  • Clavulanic acid + Sulbactam + Tazobactam – Beta-lactamase inhibitors which protect penicillins

 

e.g. Co-Amoxiclav = Amoxicillin + Clavulanic acid                  – Tazosin = Piperacillin + Tazobactam

 

  • Cephalosporins:

These have the same mechanism of action as penicillins. They exist in many generations, with each successive generation increasingly resistant to penicillinases.

 

  • Cephalexin – activity against some Gram +ve and –ve organisms
  • Ceftriaxone – enhanced activity against Gram –ve organisms, can cross BBB so treats meningitis

 

Side effects: May cause superinfection – commonest cause of hospital acquired C-difficile colitis

– Alcohol intolerance

– People allergic to penicillins should also avoid cephalosporins

 

  • Aztreonam – Beta-lactam antibiotic resistant to B-lactamases used to treat Gram –ve infections

 

  • Carbapenem + Meropenem – effective broad-spectrum antibiotics used to treat severe infections

Side effects: Can cause seizures

b) Other inhibitors of cell wall synthesis

  • Vancomycin/Teicoplanin – These are Glycopeptide antibiotics which prevent the peptidoglycan strand

from growing by binding D-Ala-D-Ala, making it unavailable to the transpeptidase enzyme.

– Used against Gram Positive infections in patients allergic to penicillin + cephalosporins

– Used to treat antibiotic resistant C. difficile + serious MRSA infections

 

Side effects: Anaphylactic like “red neck” syndrome –> due to release of histamine

– Nephrotoxicity            – Ototoxicity     – Thrombophlebitis        – 5-HT syndrome

 

There are newer antibiotics which are used to treat vancomycin resistant bacteria:

  • Linezolid – Binds 50s subunit to stop protein synthesis.

– It has been used to treat MRSA, VRE and multi-drug resistant pneumonia

Side effects: Can cause serotonin (5-HT) syndrome

 

  • Synercid – This inhibits protein synthesis and also treats MRSA, VRE and resistant streptococci

 

  • Quinupristin/Dalfopristin – This is a combination of 2 antibiotics used to treat VRE and staphylococci

– They bind different sites on the 50S ribosomal subunit inhibiting protein synthesis

Side effects: Can cause C. difficile diarrhoea and allergic reaction

 

There are some other antibiotics which are used for more simple infections:

  • Bacitracin – Antibiotic which prevents recycling of the scaffold for the pentapeptide

 

  • Cycloserine – This inhibits synthesis of the D-Ala-D-Ala- pentapeptide precursor

– Used as a second line against TB and UTI

 

  • Fosfomycin –inhibits production of the pentapeptide precursor which is used to made peptidoglycan.

– Used to treat simple urinary tract infections

c) Target Folic Acid Synthesis

The synthesis of tetrahydrofolate is essential, as it is needed to make dTMP which is needed thymine to make DNA.

– Bacteria must make the folate skeleton themselves, whereas humans can eat it in their diet.

– Synthesis is achieved by 2 key enzymes, dihydropteroate synthase and dihydrofolate reductase.

– Therefore, this pathway is targeted to prevent DNA synthesis stopping bacterial replication.

 

Therefore, there is a group of antibiotics, called sulphonamides which specifically target this pathway:

  • Sulfamethoxazole – This is an analogue of para-aminobenzoate

– It inhibits dihydropteroate synthase to prevent folic acid synthesis

 

  • Trimethoprim – This is an inhibitor of dihydrofolate reductase

– Teratogenic in the first trimester of pregnancy so avoided + gives transient rise in creatinine (not AKI)

 

  • Co-trimoxazole – This is a combination of sulfamethoxazole + trimethoprim

– The combination causes very fast depletion of tetrahydrofolate and is very effective.

 

These drugs inhibit both Gram +ve and –ve bacteria and are commonly used to treat urinary tract infections.

– Versions of these drugs are also used to treat fungi pneumocystis and toxoplasma

 

Side effects:

– Can cause hypersensitivity –> rashes, pruritus and Stevens Johnson syndrome

– Suppression of haematopoiesis –> gives megaloblastic anaemia + Leukopenia

 

d) Target DNA Replication

i) DNA topoisomerase inhibitors – topoisomerases are enzymes which organise the DNA

  • FluoroquinolonesCiprofloxacin + Levofloxacin

This inhibits the bacterial topoisomerase and so interferes with DNA replication

 

Side effects: Cartilage toxicity – weak tendons and tendonitis

Lengthens QT interval             – Lowers seizure threshold in patients with epilepsy

 

ii) DNA transcription inhibitors – Bacteria use a bacterial RNA polymerase to make mRNA

  • Rifampin – Binds to bacterial DNA-dependent RNA polymerase to stop RNA synthesis

Side effects: Body secretions turned orange + Hepatitis (inducer of CYP 450 enzyme)

 

iii) DNA interactors – These drugs can bind covalently/non-covalently causing DNA crosslinking and damage, leading to the disruption of translation and replication

  • Nitrofurantoin – This causes bacterial DNA damage by an unknown mechanism.

Side effects: Lower lobe pulmonary fibrosis (but can be taken during pregnancy)

 

  • MetronidazoleThis inhibits DNA synthesis and is used mainly against anaerobic bacteria

Side effects: Disulfiram-like reaction with alcohol

 

e) Target Protein Biosynthesis

Antibiotics that inhibit protein synthesis are usually bacteriostatic.

– During protein synthesis, the 30s subunit binds mRNA to form the initiation complex.

– The 50s subunit then joins with the aminoacyl-tRNA and uses enzyme peptidyl transferase for elongation.

– Antibiotics typically target the 30s or 50s subunit of the bacterial ribosome which is unique to bacteria:

  • Aminoglycosides [30S Subunit] – Streptomycin / Gentamycin/ Amikacin

These bind to the 30S subunit in the initiation complex, which causes misreading of the mRNA stopping protein synthesis

– They are used to treat many Gram-negative infections.

Side effects: Ototoxicity + Nephrotoxicity

 

  • Tetracyclines [30S Subunit] Lymecycline (-cycline)

These bind to the 30s subunit and stop binding of the tRNA

– They are used against both Gram-negative and positive bacteria

– Not be taken alongside milk or iron containing foods as Ca2+ and Fe2+ reduce antibiotic absorption in the gut.

 

Side effects: Photosensitivity

– Teeth discoloration so not used in children

  • Chloramphenicol [50S Subunit]

This binds the 50s subunit inhibiting peptidyl transferase

– Very broad-spectrum antibiotic, but limited to infections that cannot be treated with other drugs

 

Side effects – Aplastic anaemia

– Grey baby syndrome – babies lack the enzyme to conjugate the antibiotic in the liver. Hence it builds up in the blood causing shock and cyanosis.

 

  • MacrolidesErythromycin (-thromycin) [50S Subunit]

These drugs also bind the 50s subunit and inhibit bacterial protein elongation.

– They are commonly used against Gram-positive organisms in people who are allergic to penicillin

 Side effects: Nausea + inhibits CYPP450 enzyme + Prolong QT interval + gives reaction with statin

 

  • Clindamycin [50S Subunit]

This acts very similarly to macrolides and is used mainly against anaerobic bacteria.

Side effects: C. difficile infection (diarrhoea)

f) Targeting Mycobacteria

Mycobacteria are a subset of bacteria which are aerobic and typically very difficult to treat using standard antibiotics.

– Unlike Gram +ve/-ve bacteria, they do not Gram stain as they have a very thick waxy lipid coat on their exterior –> hence called Gram fast.

– They have a cell wall made of mycolic acid, unique to mycobacteria

  • Isoniazid (INH) – A prodrug that becomes activated in M. Tuberculosis

– Inhibits synthesis of mycobacterial cell wall by stopping enzyme needed for mycolic acid synthesis

 

Side effects: It inhibits formation of active pyridoxine (Vitamin B6) causing peripheral neuropathy

                       – Therefore, it is given with prophylactic pyridoxine

                       – Hepatitis + Inhibits CYP450 enzyme

 

  • Rifampicin/Rifampin – Binds to bacterial DNA-dependent RNA polymerase to stop RNA synthesis

– Used in combination to treat TB and also in prophylactic treatment of meningococci + H. Influenzae

 

Side effects: Body secretions are coloured orange (e.g. stains contact lenses)

– Hepatitis + Induces CYP450 enzyme           – Flu-like symptoms

 

  • Pyrazinamide – This inhibits mycobacterial cell wall formation by targeting mycolic acid synthesis

– It is effective in the acidic pH of phagosomes, where engulfed mycobacteria are found in macrophages.

 

Side effects: Hepatitis + Arthralgia

     – Inhibits uric acid secretion giving hyperuricaemia leading to gout (taken with probenecid)

 

  • Ethambutol – This inhibits key enzymes involved in mycolic acid cell wall biosynthesis.

 

Side effects: Causes optic neuritis (e.g. colour blindness, visual acuity)

– Important to pre-test visual acuity and continue to monitor throughout treatment, especially in renal failure, as kidney impairment can reduce the excretion of ethambutol.

1. https://drug.wellingtonicu.com/PDF/WellingtonDrugManual-v3-2019.pdf

Sign up to our mailing list to get an exclusive 10% discount on In2Med courses!