Over view of antimicrobial agents and their actions
If bacteria make it past our immune system and start
reproducing inside our bodies, they cause disease.
Certain bacteria produce chemicals that damage or
disable parts of our bodies.
Antibiotics work to kill bacteria. Antibiotics are specific to certain bacteria and disrupt their function.
What is an Antibiotic?
These are natural metabolic products of fungi, Actinomycetes and bacteria that kill or inhibit the growth of microorganisms. It is a selective poison.
It will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways.
In 1928, Sir Alexander Fleming, a Scottish biologist, observed that Penicillium notatum, a common mold, had destroyed Staphylococcus bacteria in culture.
Sir Alexander Fleming, Ernst Boris Chain, and Sir Howard Walter Florey were awarded the 1945 Nobel Prize in Medicine "for the discovery of penicillin and its curative effect in various infectious diseases."
Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity The most important concept underlying antimicrobial therapy is ―Selective toxicity‖ which was proposed by Paul Ehrlich.
This is achieved by exploiting the difference between the metabolism and structure of the microorganism and host cells.
e.g. penicillins and cephalosporins are effective antibacterial agents because they prevent the synthesis of peptidoglycan, thereby inhibiting the growth of bacterial cell but not human cells. This implies that the biochemical processes in the bacteria are in some way different from those in the animal cells, and that the advantage of this difference can be taken in chemotherapy.
Characteristics of Antibiotics
weight substances that are produced as secondary metabolites by certain groups of microorganisms, especially
And a few molds -Penicillium
are inhabitants of soils
Antibiotics may have a – Cidal (killing) effect or Static (inhibitory) effect on a range of microbes. The range of bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its spectrum of action.
Spectrum of action: Antibiotics effective against prokaryotes which kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum. If effective mainly against Gram-positive or Gram-negative bacteria, they are narrow spectrum. If effective against a single organism or disease, they are referred to as limited spectrum.
Antibiotic Spectrum of Activity
No antibiotic is effective against all microbes
A clinically-useful antibiotic should have as many of these characteristics as possible. 1. It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms. 2. It should be nontoxic to the host and without undesirable side effects. 3. It should be non allergic to the host. 4. It should not eliminate the normal flora of the host.
5. It should be able to reach the part of the human body where the infection is occurring. 6. It should be inexpensive and easy to produce. 7. It should be chemically-stable (have a long shelf-life). 8. Microbial resistance is uncommon and unlikely to develop.
Two groups of antimicrobial agents used in the treatment of infectious disease: Antibiotics: which are natural substances produced by certain groups of microorganisms,
Chemotherapeutic agents: which are chemically synthesized •Semisynthetic antibiotic: wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. •Synthetic antibiotics : some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means.
Microbial Sources of Antibiotics
Mechanisms of Action:
Most antibiotics act by selectively interfering with the synthesis of one of the large-molecule constituents of the cell— The cell wall synthesis Cell membrane function Proteins
Some important and clinically useful drugs interfere with the synthesis of peptidoglycan, the most important component of the cell wall.
Antibiotics can be classified into five categoriesPenicillins: e.g. Amoxycillin, Amoxil, Augmentin, Calvepen
e.g. Cefodox, Distaclor, Keflex, Zinnat Aminoglycosides: e.g. Genticin Tetracyclines e.g. Clinimycin, Hostacycline, Minocin Others: e.g. Cipro, Erymax, Erythrocin
Antimicrobial Agents Used in the Treatment of Infectious Disease
1. Cell wall synthesis inhibitors : Cell wall synthesis inhibitors generally inhibit some step in the synthesis of bacterial peptidoglycan. Generally they exert their selective toxicity against eubacteria because human cells lack cell walls.
Beta lactam antibiotics: Chemically, these antibiotics contain a 4-membered beta-lactam ring.
They are the products of two groups of fungiPenicillium - penicillins Cephalosporium molds - cephalosporins Act by inhibiting Transpeptidases, the enzyme that catalyze the final cross-linking step in the synthesis of peptidoglycan.
b Lactam Basic Structure
Penicillins: Properties Penicillins contain a β-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-positive organisms) Penicillins are bactericidal but can act only on dividing cells. They are more active during the log phase of bacterial cell growth. They are not toxic to animal cells which have no cell wall
Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis)
Resistance This is the result of production of β-lactamase in the bacteria which destroys the β-lactam ring It occurs in e.g. Staphylococcus aureus,
Haemophilus influenzae Neisseria gonorrhoea
Natural penicillins: such as Penicillin G or Penicillin V
produced by fermentation of Penicillium chrysogenum. They are effective against Streptococcus, Gonococcus and Staphylococcus. They are considered narrow spectrum since they are not effective against Gram-negative rods.
Benzylpenicillin (Penicillin G) is acid labile and βlactamase sensitive and is given only parenterally It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes,
S. pneumoniae, Neisseria meningitis N. gonorrhoeae, Treponemes, Listeria, Actinomycetes, Clostridia
Phenoxymethylpenicillin (Penicillin V) is acid stable and is
given orally for minor infections It is otherwise similar to benzylpenicillin Semi synthetic penicillins: First appeared in 1959. A mold produces the main part of the molecule (6aminopenicillanic acid) which can be modified chemically by the addition of side chains.
Many of these compounds have been developed to have distinct benefits or advantages over penicillin G,
such as increased spectrum of activity (effectiveness against Gram-negative rods) resistance to penicillinase effectiveness when administered orally
Amoxycillin Ampicillin have broadened spectra against Gramnegatives and are effective orally; Methicillin is penicillinase-resistant.
Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those above)
Strept. faecalis, Haemophilus influenza, E. coli, Klebsiella Proteus strains
It is acid stable, is given orally or parenterally, but is βlaclamase sensitive
Amoxycillin is similar but better absorbed orally
It is sometimes combined with clavulanic acid, which is a β-lactam with little antibacterial effect but which binds strongly to β-lactamase and blocks the action of βlactamase in this way
It extends the spectrum of amoxycillin
Clavulanic acid: Is a chemical sometimes added to a semi synthetic penicillin preparation. Amoxycillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams. Although nontoxic, penicillins occasionally cause death when administered to persons who are allergic to them. In the U.S. there are 300 - 500 deaths annually due to penicillin allergy. In allergic individuals the beta lactam molecule attaches to a serum protein which initiates an IgE-mediated inflammatory response.
Bacitracin: Is a polypeptide antibiotic produced by Bacillus species.
It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
Glycopeptides: Vancomycin-- appear to inhibit both transglycosylation and transpeptidation reactions during peptidoglycan assembly. They bind to the muropeptide subunit as it is transferred out of the cell cytoplasm and inhibit subsequent polymerization reactions. Vancomycin is not effective against Gram-negative bacteria because it cannot penetrate their outer membrane. It has become important in clinical usage for treatment of infections by strains of Staphylococcus aureus that are resistant to virtually all other antibiotics.
Azlocillin is acid labile and is only used parenterally
It is β-lactamase sensitive and has a broad spectrum, which includes - Pseudomonas aeruginosa Proteus species It is used intravenously for life-threatening infections, i.e. in immunocompromised patients together with an aminoglycoside
Adverse effects Allergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effects Superinfections (e.g. caused by Candida ) Diarrhoea : especially with ampicillin, less common with amoxycillin
Rare: haemolysis, nephritis
Cephalosporins They also owe their activity to β-lactam ring and are bactericidal. Good alternatives to penicillins when a broad -spectrum drug is required Should not be used as first choice unless the organism is known to be sensitive
BACTERICIDAL- modify cell wall synthesis
CLASSIFICATIONFirst generation are early compounds Second generation- resistant to β-lactamases Third generation- resistant to β-lactamases & increased spectrum of activity Fourth generation- increased spectrum of activity
FIRST GENERATION- e.g. cefadroxil, cefalexin, Cefadrine - most active against Gram positive cocci. An alternative to penicillins for staph and strep infections; useful in UTIs
SECOND GENERATION- e.g. cefaclor and cefuroxime. Active against Enterobacteriaceae eg E. coli,
Klebsiella spp, Proteus spp. May be active against H influenzae and N meningtidis
THIRD GENERATION- eg cefixime and other I.V.s cefotaxime, ceftriaxone, ceftazidine. Very broad spectrum of activity - Gram negative rods less activity - Gram positive organisms.
FOURTH GENERATION- cefpirome better against Gram positive than 3rd generation. Also better against Gram negative bacteria Enterobacteriaceae & Pseudomonas aerugenosa. I.V. route only
Adverse effects Allergy (10-20% of patients wit penicillin allergy are also allergic to cephalosporins) Nephritis and acute renal failure Superinfections Gastrointestinal upsets when given orally
Two other classes of beta lactams are the carbapenems and monobactams. The monobactams are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy.
2. Cell membrane inhibitors
These antibiotics disorganize the structure or inhibit the function of bacterial membranes.
The integrity of the cytoplasmic and outer membranes is vital to bacteria, and compounds that disorganize the membranes rapidly kill the cells. The only antibacterial antibiotic of clinical importance that acts by this mechanism is polymyxin, produced by Bacillus polymyxis.
Polymyxin is effective mainly against Gram-negative bacteria and is usually limited to topical usage.
Polymyxin binds to membrane phospholipids and thereby interferes with membrane function.
Polymyxin is occasionally given for UTI caused by Pseudomonas strains that are gentamicin, carbenicillin and tobramycin resistant.
The balance between effectiveness and damage to the kidney and other organs is dangerously close, and the drug should only be given under close supervision in the hospital
3. Protein synthesis inhibitors
Many therapeutically useful antibiotics owe their action to inhibition of some step in the complex process of protein synthesis. Their attack is always at one of the events occurring on the ribosome and never at the stage of amino acid activation or attachment to a particular tRNA. Most have an affinity or specificity for 70S ribosomes, and they achieve their selective toxicity in this manner.
The most important antibiotics with this mode of action are the tetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and the aminoglycosides (e.g. streptomycin).
The aminoglycosides are products of Streptomyces species and are represented by streptomycin, kanamycin, tobramycin and gentamicin. These antibiotics exert their activity by binding to bacterial ribosomes and preventing the initiation of protein synthesis.
Aminoglycosides (bactericidal) Streptomycin Kanamycin Gentamicin Tobramycin Amikacin Netilmicin Neomycin (topical)
Mode of action –
The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA), no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. May also destabilize bacterial membranes.
Spectrum of Activity -Many Gram-negative and some Gram-positive bacteria
Resistance - Common Synergy - The aminoglycosides synergize with β-lactam antibiotics. The β-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.
Kanamycin and tobramycin: have been reported to bind to the ribosomal 30S subunit and to prevent it from joining to the 50S subunit during protein synthesis.
Kanamycin (a complex of three antibiotics, A, B and C) is active at low concentrations against many Grampositive bacteria, including penicillin-resistant staphylococci.
They may have a bactericidal effect because this leads to cytoplasmic accumulation of dissociated 30S subunits, which is apparently lethal to the cells. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis.
Gentamicin (a mixture of 3 components) is active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. e.g. Enteric organisms (E.coli, Klebsiella, S. faecalis,
Pseudomonas and Proteus spp.)
It is also used in antibiotic combination against Staphylococcus aureus. It is not active against aerobic Streptococci. Gentamicin and Tobramycin are mainstays for treatment of Pseudomonas infections.
An unfortunate side effect of aminoglycosides has tended to restrict their usage: prolonged use is known to impair kidney function and cause damage to the auditory nerves leading to deafness
Tobramycin: used for pseudomonas and for some
Some aminoglycosides,e.g. Gentamicin, may also be applied topically for local effect, e.g. In ear and eye ointments.
Neomycin is used orally for decontamination of
Although effective, aminoglycosides are toxic, and this is plasma concentration related. The main adverse effects are: Nephrotoxicity Toxic to the 8th cranial nerve (ototoxic), especially the vestibular division.
Other adverse effects are not dose related, and are relatively rare, e.g. Allergies, eosinophilia.
Tetracyclines (bacteriostatic) tetracycline, minocycline and doxycycline
Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. Spectrum of activity - Broad spectrum with a wide range of activity against both Gram-positive and Gram-negative bacteria. Useful against intracellular bacteria
Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.
The tetracyclines :
consist of eight related antibiotics which are all natural products of Streptomyces, Some can now be produced semisynthetically or synthetically. Tetracycline, chlortetracycline and doxycycline are the best known.
Their most common use today is for acne, given either orally or topically.
Doxycycline has a longer half-life and can be given once
They are specially indicated for Mycoplasma, Rikettsia, Chlamydia and Brucella infections. They should be taken at least half an hour before food. Tetracyclines concentrate in bones and teeth.
Discolouration and deformity in growing teeth and bones (contraindicated in pregnancy and in children < 12 years) Renal impairment (should be also avoided in renal disease)
Is a protein synthesis inhibitor has a broad spectrum of activity but it exerts a bacteriostatic effect. It inhibits the bacterial enzyme peptidyl transferase, thereby preventing the growth of the polypeptide chain during protein synthesis. It is effective against intracellular parasites such as the rickettsiae.
Unfortunately, aplastic anemia, which is dose-related develops in a small proportion (1/50,000) of patients.
Chloramphenicol was originally discovered and purified from the fermentation of a Streptomyces But currently it is produced entirely by chemical synthesis.
The major indication is to treat bacterial meningitis caused by Haemophilus influenzae, or to Neisseria menigitidis or if organism is unknown. It is also specially used for Rikettsia (typhus).
A rare anemia, probably immunological in origin but often fatal Reversible bone marrow depression caused by its effect on protein synthesis in humans Liver enzyme inhibition
Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin
Mode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunit
Spectrum of activity - Gram-positive bacteria,
Mycoplasma, Legionella (intracellular bacterias)
Resistance - Common
Erythromycin: is acid labile but is given as an enterically coated tablet
Absorption is erratic and poor.
It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract (enterohepatic circulation). It may be given orally or parenterally
Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid
The spectrum includes Staphylococcus aureus,
Streptococcuss pyogenes, S. pneumoniae, Mycoplasma pneumoniae and Chlamydia infections.
Newer macrolides such as clarithromycin and azithromycin may have fewer adverse effects
Macrolides – side effects
Nauzea, vomitus Allergy Hepatitis
4. Effects on Nucleic Acids
Some antibiotics and chemotherapeutic agents affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. The majority of these drugs are unselective, however, and affect animal cells and bacterial cells alike and therefore have no therapeutic application. Two nucleic acid synthesis inhibitors which have selective activity against procaryotes and some medical utility are the quinolones and rifamycins.
Nalidixic acid is a synthetic chemotherapeutic agent which has activity mainly against Gram-negative bacteria.
Nalidixic acid belongs to a group of compounds called quinolones.
Nalidixic acid is a bactericidal agent that binds to the DNA gyrase enzyme (topoisomerase) which is essential for DNA replication and allows super coils to be relaxed and reformed Binding of the drug inhibits DNA gyrase activity.
The quinolones are effective but expensive antibiotics. With increased use, resistance to these drugs is becoming more common. They should in general be reverse drugs and not first-line treatment.
Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower UTI, as it has no systemic antibacterial effect.
The compound is effective against several types of Gramnegative bacteria which are common causes of UTI such as
E. coli, Enterobacter aerogenes, K. pneumoniae Proteus species
It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria are resistant.
Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas.
It can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such as peritonitis and Salmonella. It was recently touted as the drug of choice for treatment and prophylaxis of anthrax. Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.
Gastrointestinal upsets They are also contraindicated in epileptics. Allergy and anaphylaxis. Possibly damage to growing cartilage: not recommended for pregnant women and children.
The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces.
Rifampicin is a semisynthetic derivative of rifamycin that is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells.
The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M .tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis.
Competitive Inhibitors Many of the synthetic chemotherapeutic agents are competitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism.
These types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs They are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite
They do not fulfill their metabolic function in the cell.
Some are bacteriostatic and some are bactericidal.
Sulfonamides, Sulfones (bacteriostatic)
Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Spectrum of activity - Broad range activity against grampositive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
Trimethoprim, Methotrexate, (bacteriostatic) Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.
Spectrum of activity - Broad range activity against grampositive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.
Resistance - Common Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
p-aminobenzoic acid + Pteridine Sulfonamides
Dihydropteroic acid Dihydrofolate synthetase Dihydrofolic acid Trimethoprim Dihydrofolate reductase
Tetrahydrofolic acid Thymidine
Cotrimoxazole is widely used for urinary and upper respiratory tract infections but should not be the drug of choice because of its adverse effects.
It is the drug of choice for the treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients. Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective.
Adverse effects Gastrointestinal upsets
Less common but more serious: - Sulfonamides: allergy, rash, fever, agranulocytosis, renal toxicity - Trimethoprim: macrocytis anemia, thrombocytopenia - Cotrimoxazole: aplastic anemia