Pharmaceutical Microbiology


Structure of penicillin

Antibacterial agents are specifically chemical agents that kill or inhibit the growth of pathogenic bacteria. They are generally known as antibiotics. Antibiotics are complex chemical and natural substances that are secreted by some group of microorganisms (especially fungi, protozoa and bacteria), and which have the ability to either kill or inhibit the growth of other microbes. Prior to the manufacture of synthetic and semi-synthetic antibiotics, antibiotics were formerly defined as substances produced by microorganisms and which killed or inhibited the growth of other microbes. Though there is no census to the actual definition of antibiotics; to be all encompassing, an antibioticcan best be defined as a substance produced by a microorganism (wholly or partly by chemical synthesis) which in low or defined concentrations have the ability to kill or inhibit the growth of other susceptible microbes. The term antibiotics can synonymously be used with antimicrobial agents. Penicillin and tetracycline are examples of some naturally synthesized antibiotics produced by Penicillium species and Streptomyces species respectively. However, some of the available antibiotics are now synthesized by chemical processes using derivatives from their natural or original sources. Antibiotics are either used topically or systemically; and their primary function is to kill or inhibit the growth of invading pathogenic bacteria in humans. Antibiotics are secondary metabolites produced by bacteria. They destabilize certain metabolic process of their target organisms, and thus restore the health of the affected host. It is noteworthy that the bacteria that produce these antimicrobial agents remain resistant to their own lethal substance, but they are susceptible to the antibiotics secreted by other bacterial species or microbes. Antibiotics can be classified as cell wall inhibitors; protein synthesis inhibitors; anti-metabolites or nucleic acid synthesis inhibitors depending on the mechanism of action of the drug. Other classes of antibiotics also target the cytoplasmic or plasma membrane of the bacterial cell. Different antibiotics have different modes or mechanisms of action, owing to the nature of their structure and degree of affinity to certain target sites within bacterial cells. Antimicrobial agents and/or antibiotics are critical for the selective isolation of microbes from both clinical and environmental samples. Antibiotics are incorporated into culture media including bacteriological and mycological media to act as inhibitory substances to the growth of some unwanted organisms (Table 1). They are mainly used in culture media generally known as selective culture media (culture media that allow some organisms to grow while inhibiting the growth of unwanted microbes).

 Table 1. Antibiotics used in selective culture media as inhibitory substances

Antibiotics Spectrum of activity Mechanism of action
Penicillin Active on Gram positive and Gram negative bacteria, but mostly active on the former Inhibits bacterial cell wall synthesis by preventing the formation of peptidoglycan, a key cell wall component
Tetracycline Broad spectrum agent Inhibits protein synthesis in bacteria by binding to the 30S ribosomal subunit
Novobiocin Active on Gram-negative bacteria Inhibits bacterial DNA synthesis
Chloramphenicol Broad spectrum agent Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit
Streptomycin Broad spectrum agent Inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit
Erythromycin Mostly active on Gram positive bacteria Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit
Polymyxin Active on Gram negative bacteria especially Pseudomonas species Disrupts cell membrane of bacteria
Rifampicin Active on Gram positive bacteria Inhibit bacterial RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase enzyme
Nalidixic acid Active on Gram negative bacteria Inhibits bacterial DNA synthesis by interfering with the activity of DNA gyrase
Trimethoprim Broad spectrum agent Inhibit purine synthesis in bacteria
Cycloheximide Active on saprophytic fungi Inhibit protein biosynthesis in eukaryotic organisms such as fungi by interfering with the translocation step in protein synthesis. It inhibits translation elongation through binding to the E-site of the 60S ribosomal unit and interfering with deacetylated tRNA (1-3)


Antibiotics in this category disrupt the cell wall of bacteria (inclusive of Gram positive and Gram negative bacteria). Examples of antibiotics that are cell wall inhibitors include: penicillins, cephalosporins, vancomycin, monobactams and other anti-mycobacterial agents that specifically target the cell wall of mycobacteria (whose cell wall contain mycolic acid). Antibiotics that are cell wall inhibitors are only effective against bacteria with cell wall. They have no activity on bacteria that do not have cell wall (e.g. mycoplasmas). Cell wall inhibitors basically stop the synthesis of peptidoglycan in bacteria, and this ultimately prevents their cell wall (a natural barrier that controls the flow of molecules in- and out- of the cell) from forming.


Protein synthesis inhibitors interact with the ribosomes of bacteria (especially the 50S and 30S ribosomes); and this interactions prevents translation in the target bacterial cells. Translation is vital for protein synthesis because it is at this stage that the genetic information encoded by the DNA is decoded by the mRNA for the formation of a specific protein molecule. Bacterial ribosomes are usually 30S, 50S and 70S while the ribosomes of eukaryotic cells particularly humans is 80S. Note: The “S” values attached to the 50S ribosomes or ribosomal subunit is generally referred to Svedberg units; and it shows the sedimentation coefficients of ribosomal subunits (e.g. 30S, 50S and 70S) when they are subjected to centrifugal force in an ultracentrifuge. Streptomycin, chloramphenicol, tetracyclines and erythromycins amongst others are typical examples of antibiotics that are protein synthesis inhibitors but each is specific in action in that they target specific ribosomal subunit of the bacterial cell either 50S or 30S ribosomal subunit.


Some antibiotics target only the cell membranes of bacteria cells. Examples include the polymyxins. The integrity of the cytoplasmic or plasma membrane is vital for the normal functioning of all bacterial cells. Cytoplasmic membranes act as diffusion barriers to some molecules including water, antibiotics and nutrients. But antibiotics that target bacterial cell membranes destabilizes the plasma membrane, and makes it more permeable to harmful substances including antibiotics that destroy the cell.


Nucleic acid inhibitors are group of antibiotics that target the DNA of bacterial cells. Typical examples of nucleic acid inhibitors include rifampicin, ciprofloxacin and a range of other antimicrobial drugs. Nucleic acid inhibitors target the DNA and RNA synthesis of bacterial cells especially by disrupting the activities of key enzymes required for these processes especially DNA gyrase (topoisomerase II and IV) and RNA polymerase. DNA gyrase enzyme and/or topoisomerases are crucial for the synthesis of nucleic acids (particularly DNA) in bacterial cells; and when their natural activity is interfered with, DNA synthesis will be interrupted. Because the activities of the cell is mainly directed by the DNA (which is the actual genetic material), the bacterial cell will die once its ability to synthesize nucleic acid molecules have been disrupted.


Anti-metabolites are antibiotics that inhibit the metabolic pathways of pathogenic bacteria especially as it relates to the biosynthesis of important molecules in the microbes. They are basically sulpha drugs that interfere with the metabolic pathways responsible for synthesizing important growth molecules (e.g. folic acid) in bacterial cells. Trimethoprim, pyrimethamine and sulphamethoxazole are typical examples of antimetabolites. Generally, anti-metabolites compete for essential metabolites, nutrient molecules or growth factors that are considered necessary in bacterial metabolism especially as it relates to their unperturbed development. Antibiotics in this category are chemically synthesized drugs i.e. they are synthetic agents.        


 Antibiotics can also be classified into different categories depending on their mode of action and/or spectrum of activity. In this section, the different classes of antibiotics based on their functional groups shall be highlighted.


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; and 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, and this binding interferes with the transpeptidases enzymes involved in transpeptidation reaction- which 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, and thus 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, and 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. Beta-lactam antibiotics inhibit some basic steps in the synthesis of cell wall in bacterial cell especially as it relates to the peptidoglycan and murein components. They are active against both Gram positive and Gram negative bacteria; and thus beta-lactam drugs are bacteriocidal in action.


Macrolides include erythromycin and azithromycin; and they are naturally-synthesized antibiotics produced by Streptomyces species (e.g. Streptomyces erythreus). They specifically inhibit translation i.e. 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; and this feature differentiate 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; and 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.


Quinolones include nalidixic acid, oxolinic acid and conoxacin. Quinolones are synthetic antibiotics that have activity against Gram negative bacteria; and they mainly inhibit DNA replication in bacterial cells by targeting the key enzymes (e.g. DNA gyrase enzyme 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 are fluorinated derivatives of quinolones and 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; and 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; and 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.


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; and members of 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 today.


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 and the bacteria genus Micromonospora which synthesize gentamicin. Tobramycin, neomycin, amikacin and kanamycin are other examples of aminoglycosides. Aminoglycosides are bacteriocidal in action and they are broad spectrum antibiotics; but they 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 to enter the cell and unleash its antimicrobial activity.


Sulphonamides are structural analogues of Para-Aminobenzoic Acid (PABA) which is required for the synthesis of folic acid in bacteria. Folic acid is required as a cofactor for the synthesis of nucleotides, and they also act as building blocks for bacterial DNA and RNA. However, prokaryotic cells (particularly bacteria) synthesize their own folic acid molecules unlike eukaryotic cells which obtain theirs from their food intake; and 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); thus disrupt 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.

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