STRUCTURAL CLASSIFICATION OF ANTIBACTERIAL AGENTS

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Antibacterial agents can also be classified into different categories based on their shared molecular structure and based on their mode of action and/or spectrum of activity. In this classification, antibacterial agents with similar molecular structure and mechanism of action are classified under one particular category. For example, antibacterial agents known as beta-lactam agents have a common molecular structure known as the beta-lactam ring. This molecular structure of the beta-lactams is shared by all antibacterial agents in this class known as beta-lactam agents. Aside, their spectrum of activity or mode of action, antibacterial agents can also be classified based on their source. According to their source, antibacterial agents can be classified as natural antibacterial agents, synthetic antibacterial agents or semi-synthetic antibacterial agents. However, in this section, the different classes of antibacterial agents based on their functional groups and molecular structure shall be highlighted.

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  • BETA-LACTAM ANTIBIOTICS

Beta-lactam antibiotics are group of naturally-synthesized antibiotics that inhibit the synthesis of cell wall in bacteria. Some later beta-lactam drugs such as methicillin, ampicillin and amoxicillin amongst others are synthesized by chemical processes. Beta-lactam drugs contain a 4-membered beta lactam ring. This beta-lactam ring is usually the main target of some antibiotic degrading enzymes such as the beta-lactamases. The 4-membered beta-lactam ring is the main component of the structure of all beta-lactam antibiotics. Antibiotics in this category bind to the penicillin-binding-proteins (PBPs) of the bacterial cell wall. This binding interferes with the transpeptidases enzymes involved in transpeptidation reaction. Transpeptidation reaction is vital for the cross-linking of N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG) molecules required for the formation of peptidoglycan (that maintains the integrity of the bacterial cell through the formation of cell wall).

Beta-lactam antibiotics are bacteriocidal agent. They kill bacterial cells by preventing the formation of cell walls. Prevention of the formation of a cell wall leaves a bacteria cell porous to attack from its environment. This leads to lysis of the cell due to external pressure from the outside. And this could be as a result of differences in the osmotic pressure of the internal environment of the cell and that of its external environment which allows different molecules to gain entry into the cell’s internal environment. Bacterial cells could swell and rupture or lyse (i.e. die) in this manner. Typical examples of antibiotics that are beta-lactams are penicillins and cephalosporins which are mainly produced naturally by two fungi genera: Penicillium and Cephalosporium respectively. Beta-lactam antibiotics inhibit some basic steps in the synthesis of cell wall in bacterial cell especially as it relates to the formation of peptidoglycan and murein components. They are active against both Gram-positive and Gram-negative bacteria; and this makes beta-lactam drugs to be bacteriocidal in action.

  • MACROLIDES

Macrolides include erythromycin and azithromycin. They are naturally-synthesized antibiotics produced by Streptomyces species such as Streptomyces erythreus. Erythromycin is naturally sourced from S. erythreus.Macrolides specifically inhibit translation, thereby inhibiting protein synthesis in bacterial cells. Antibiotics that are macrolides are known to contain large lactone rings that are linked through glycoside bonds with amino sugars. This feature differentiates them from beta-lactam drugs that contain a 4-membered beta-lactam ring. Macrolides are mostly bacteriostatic agents, but some are cidal in action against some Gram-positive bacteria. Lincomycin and clindamycin are other examples of macrolides that also inhibit protein synthesis in bacterial cells. Macrolides generally inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. This interferes with the activity of peptidyl transferase which is supposed to stimulate the elongation of the protein molecules in the bacterial cell. Chloramphenicol is another example of antibiotic that target the 50S ribosomal subunit of bacteria. However, chloramphenicol is not a macrolide.         

  • QUINOLONES

Quinolones include nalidixic acid, oxolinic acid and conoxacin. Quinolones are synthetic antibiotics that have activity against Gram-negative bacteria. They mainly inhibit DNA replication in bacterial cells by targeting the key enzymes such as DNA gyrase or topoisomerases responsible for the biosynthesis of DNA molecules. They are bacteriocidal in action. Quinolones are mainly used to treat urinary tract infections (UTIs) in humans. 

  • FLUOROQUINOLONES

Fluoroquinolones are fluorinated derivatives of the quinolones. Typical examples include ciprofloxacin, ofloxacin and norfloxacin. The fluoroquinolones are mainly derived by the addition of a fluorine molecule on the carbon-6 (C-6) of the quinolone molecule. Fluoroquinolones like the quinolones are bacterial DNA replication inhibitors. They are active against Gram-negative bacteria and some Gram-positive bacteria. They are synthetic antibiotics; and like the quinolones, fluoroquinolones or 4-quinolones are bacterial DNA replication inhibitors. They inhibit DNA gyrase enzyme and topoisomerase IV which are both required for bacterial DNA replication. Fluoroquinolones are broad spectrum antibiotics and they are bacteriocidal in action. They can be used to treat a wide variety of bacterial infections including but not limited to UTIs, intestinal infections, and lower respiratory tract infections amongst others.  

  • TETRACYCLINES

The tetracyclines are group of antibiotics that block protein synthesis in bacteria by binding to the 30S ribosomal subunit. They are bacteriostatic in action but have a broad spectrum of activity. Antibiotics in this category include doxycycline, tetracycline and minocycline. Tetracyclines are structurally made up of four-fused benzene ring to which molecular substitutions are attached to generate a different type of tetracycline with unique pharmacological activity. The tetracyclines are naturally synthesized antibiotics, and they are mainly synthesized by Streptomyces species. However, tetracyclines can still be produced semi-synthetically in the laboratory.

  • AMINOGLYCOSIDES

Aminoglycosides are antibiotics that inhibit protein synthesis or translation in bacteria. They specifically bind to the 30S ribosomal subunit of bacterial ribosome. Structurally, aminoglycosides have a six-membered aminocyclitol ring to which amino sugars are attached through a glycosidic bond. The aminoglycosides are naturally synthesized antibiotics and they are mainly produced from fungi such as Streptomyces species which synthesize streptomycin andthe bacteria genus Micromonospora which synthesize gentamicin. Tobramycin, neomycin, amikacin and kanamycin are other examples of aminoglycosides. Aminoglycosides are bacteriocidal in action. They are broad spectrum antibiotics. Aminoglycosides are mainly used to treat infections caused by Gram-negative bacteria especially those in the family Enterobacteriaceae. They easily penetrate the cytoplasmic membrane of aerobic bacteria than that of anaerobic bacteria. To be effective for treating infections caused by anaerobic bacteria (e.g. Streptococcus species), aminoglycosides are combined or synergistically used with cell wall inhibitors (e.g. vancomycin and penicillin) which open the cell wall of anaerobic organisms and allow the drug (in this case: the aminoglycoside) to enter the cell and unleash its antimicrobial activity.    

  • SULPHONAMIDES

Sulphonamides are generally known as anti-metabolites because they are a class of antimicrobial agent that block the synthesis of a key metabolite in their target bacterial pathogen. They stop the target organism from utilizing a key metabolite – which is required for its basic metabolic activities. Sulphonamides are structural analogues of Para-Aminobenzoic Acid (PABA) which is required for the synthesisof folic acid in bacteria. Folic acid is required as a cofactor for thesynthesis of nucleotides. They also act as building blocks for the synthesis of bacterial DNA and RNA and protein molecules. However, prokaryotic cells (particularly bacteria) synthesize their own folic acid molecules unlike eukaryotic cells which obtain theirs from their food intake. This makes pathogenic bacteria to be more susceptible to antibiotics that are anti-metabolites. Anti-metabolites inhibit dihydropteroate synthase (the enzyme that catalyzes the conversion of PABA to folic acid or dihydropteroic acid). This disrupts folic acid synthesis in the bacterial cell. Antibiotics that are sulphonamides specifically compete for PABA in the bacterial cell; and the incorporation of sulphonamide instead of PABA by the cell inhibits the synthesis of folic acid. Thus, DNA and RNA synthesis in the bacteria will be impaired. Sulphamethoxazole, pyrimethamine, and trimethoprim are examples of antibiotics known as sulphonamides and/or anti-metabolites.

FURTHER READING

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

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