Anti-Bacterial 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).

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 peptide strands cross-link, making the cell wall strong.

This gives the bacteria the strength to withstand turgor pressure.

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

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

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 are particularly effective against Gram-positive bacteria due to their thick cell wall.

Penicillin G

This is an early penicillin which only treats Gram +ve bacteria

Flucloxacillin

A penicillin-type antibiotic which is used mainly against Staphylococcus Aureus

Ampicillin, Amoxicillin

These are extended spectrum which treat both Gram +ve and –ve bacteria

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

These are beta-lactamase inhibitors which protect penicillins

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

This has activity against some Gram +ve and –ve organisms

Ceftriaxone

This has enhanced activity against Gram negative organisms.

It can also cross the bloodbrain barrier and so is used in the treatment of meningitis.

Aztreonam

This is a beta-lactam antibiotic which is resistant to β-lactamases.

It is used to treat Gram negative infections, e.g., pseudomonas aeruginosa

Carbapenem, meropenem

These are very broad-spectrum beta-lactam antibiotics which are used to treat severe or resistant infections.

They are often used after previous antibiotics have been unsuccessful and they can lower the seizure threshold.

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 in Gram +ve infections in patients allergic to penicillin and cephalosporins.

They are also used to treat antibiotic resistant C. difficile and MRSA infections.

Target Folic Acid Synthesis

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

Bacteria must make the folate skeleton themselves, whereas humans can obtain it from their diet.

Synthesis is achieved by two key enzymes: dihydropteroate synthase and dihydrofolate reductase.

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 paraaminobenzoate.

It inhibits dihydropteroate synthase (DHPS) to stop folic acid synthesis.

Trimethoprim

This is an inhibitor of dihydrofolate reductase (DHFR)

It is often first-line for simple lower urinary tract infections.

It has teratogenic potential, especially in the first trimester of pregnancy.

Co-trimoxazole

This is a combination of sulfamethoxazole and trimethoprim.

The combination causes very fast depletion of tetrahydrofolate and is very effective for pneumocystis pneumonia (PCP).

Target DNA Replication

Fluoroquinolones – Ciprofloxacin, levofloxacin

These drugs inhibit the bacterial topoisomerase which organise the DNA.

This leads to interference with DNA replication, stopping bacteria from multiplying.

Rifampicin

This binds to bacterial DNA-dependent RNA polymerase to stop RNA synthesis

Nitrofurantoin

This causes bacterial DNA damage by an unknown mechanism. It is used in lower urinary tract infections.

Metronidazole

This inhibits DNA synthesis and is used mainly against anaerobic bacteria.

It is also useful in the treatment of intra-abdominal abscesses.

Target Protein Biosynthesis

Antibiotics that inhibit protein synthesis are usually bacteriostatic.

In protein translation, the 30S subunit binds mRNA to form the initiation complex.

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

Antibiotics typically target the 30S or 50S subunit of the bacterial ribosome, which is unique to bacteria.

Aminoglycosides – Streptomycin, gentamicin

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

They are used to treat many Gram-negative infections.

Tetracyclines – Lymecycline 

These bind to the 30S subunit and stop binding of the tRNA.

They are used against both Gram negative and positive bacteria.

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

Chloramphenicol

This is a very broad-spectrum antibiotic which binds the 50S subunit inhibiting peptidyl transferase.

It is limited to infections that cannot be treated with other drugs. 

Macrolides – Erythromycin

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

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

Clindamycin

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

Targeting Mycobacteria

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

They do not Gram stain as they have a thick external waxy lipid coat.

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

Isoniazid (INH)

This is a prodrug that becomes activated in M. tuberculosis.

It inhibits cell wall synthesis by stopping enzymes needed for mycolic acid synthesis.

Rifampicin

This binds to bacterial DNA-dependent RNA polymerase to stop RNA synthesis

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

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.

Ethambutol

This inhibits key enzymes involved in mycolic acid cell wall biosynthesis 

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