Chapter 12

 Antimicrobial Drugs

•         Chemical substances used for treatment of infectious diseases - chemotherapy

•         Antimicrobial drugs have selective toxicity (harmful against microbes and not the host)

•         Antibiotic – substance produced by one microorganism that is inhibitory or toxic against other microorganism

•         Penicillin was the first antibiotic discovered by Alexander Fleming in 1928. 

•         Mold – Penicillium notatum. Its commercial use started in 1945

•         New antibiotics are being discovered by screening large number of microbes (400,000 screened; 3 useful drugs)

Spectrum of Antibacterial Activity

•         An antibiotic can be effective against a

–        narrow group of microbes (Penicillin G – against Gram positive bacteria)

–        broad-spectrum antibiotic

•         disadvantage- eliminates also the normal microflora

Action of Antimicrobial Drugs

•         Bactericidal – kills the microbes

•         Bacteriostatic – inhibits the growth

Modes of antimicrobial action:

•         Inhibition of

–        Cell wall synthesis

–        Protein synthesis

–        Cytoplasmic membrane synthesis

–        Synthesis of essential metabolites

–        DNA synthesis

Inhibitors of cell wall synthesis

•         Penicillins and cephalosporins interfere with the formation of peptidoglycan layer in the cell wall of bacteria (not present in eucaryotic cells). Bactericidal.

•         Block the enzymes that cross-link N-acetyl glucosamin and N-acetyl muramic acid

•         Less effective against Gr negative bacteria – do not penetrate the outer membrane

Penicillins

•         Natural penicillin (Penicillin G)

•         It has a narrow spectrum (staphylococci, streptococci, and spirochetes)

•         It is rapidly excreted from the body

•         More efficient when injected than when taken orally.

•         It is susceptible to penicillinases (enzymes that cleave the penicillin molecule)

Semisynthetic penicillins

•         Partially produced by the mold Penicillium and partially by a chemical process

•         The change of the shape of the molecule makes it more difficult to break up by penicillinase.

β-Lactamase (penicillinase) action

•         Bacteria resistant to penicillins have the enzyme  b-lactamase

•         It breaks the Lactam ring

Some other cell wall inhibitors

•         Cephalosporins

–        Similar to penicillin, resistant to b-lactamase

–        Oral administration possible

•         Bacitracin

–        Polypeptide antibiotic effective against Gr + bacteria

–        Major ingredient of Neosporin – used for skin infections

Protein Synthesis Inhibitors

•         Aminoglycosides (Streptomycin)

–        Change in the 30S ribosome shape; mRNA misread

–        Isolated from Streptomyces

•         Chloramphenicol

–        Inhibits formation of polypeptide chain

–        Bacteriostatic

–        Use restricted – suppresses formation of blood cells

Tetracyclin

–        Interferes with attachment of tRNA to mRNA

–        Effective against Gr+ and Gr-

–        Bactriostatic

•         Erythromycin

–        Binds to ribosome and prevents its movement along the mRNA

–        Not effective against Gr negative bacteria

–        Bacteriostatic

Injury to Plasma Membrane

•         Polymixin B

–        changes the permeability of plasma membrane

–        Effective against Gr – bacteria -  Pseudomonas

–        Bactericidal effect

Inhibition of nucleic acid synthesis

•         Rifampin –

–        Inhibits the synthesis of mRNA

–        Used for treatment of mycobacterial infections (tuberculosis)

–        Good penetration of tissues

–        Cannot penetrate the cell envelope of Gr negative bacteria

–        Bactericidal

Inhibitors of the Synthesis of Essential Metabolites

Sulfanamides

•         Bacteria require PABA  (para-aminobenozoic acid) for synthesis of folic acid (essential for synthesis of nucleic bases)

•         A sulfanil amid drug mimics the PABA and acts as competitive inhibitor

Antifungal drugs

•         Restricted use - target the same mechanisms as those found in higher animals (protein and nucleic acid synthesis)

•         Amphotericin B is the most commonly used antifungal antibiotic

•         Produced by Streptomyces

•         It combines with sterols - components of fungal plasma membrane causing an increase of its permeability

•         The drug is toxic to kidneys

Griseofulvin

•         Produced by Penicillium

•         Effective against fungi infecting hair and nails

•         Interferes with mitosis (reproduction)

•         Binds to keratin

Antiviral drugs

•         Viruses cause 60% of infectious diseases

•         There is a limited number of antiviral drugs because viruses are endocellular pathogens

Actions of Antiviral Drugs

•         Inhibition of virus entry

–        Fuzeon – prevents binding of viral (HIV) receptor to cell receptor

–        Amantadine – prevents entry of influenza virus into cell

•         Inhibition of nucleic acid synthesis

–        Acyclovir – Purine analog – terminates DNA replication

–        Zidovudin – reverse transcriptase inhibitor (HIV)

•         Inhibition of viral assembly

–        Indinavir – protease inhibitor – prevents maturation of virus particles

Analogs of Viral DNA and RNA components

Acyclovir

•         Effective against herpesvirus (genital herpes)

•         The drug has a structure similar to guanosine nucleoside (component of DNA).

How bacteria evade the action of antibiotics?

•         Inactivation of the drug (b-lactamase)

•         Prevention of penetration

•         Efflux – pumping the drug out of the cell    video

•         Alteration of the drug’s target sites (mutation in a single amino acid in the ribosome)

Natural selection and Drug Resistance  Where does it come from?

•         Any microbial population contains individual cells with a prior mutation (drug resistance)

•         If the population is exposed to a drug – the resistant cells will eventually become dominant

The Rise of Drug Resistance

The reasons:

•         Use of antibiotics for cold or influenza

•         Patient’s failure to follow the prescribed treatment

•         Long-term, low-dose treatment of acne

•         Use of antibiotics in animal feed (antibiotics promote growth and weight gain in farm animals)

MRSA - (Methicilin Resistant Staphylococcus aureus)

•         Methicilin – the first semisynthetic penicillin

•         Designed to evade the action of penicillinase

•         Staphylococci developed resistance

•         Methicillin discontinued in the US

New Approaches to Antimicrobial Therapy

•         Probiotic approach - desirable bacteria are included in animal’s feed; this could prevent development of harmful bacteria

Side Effects of Antibiotics

•         Hearing impairment

•         Liver and kidney damage

•         Toxic effect when taken with other drugs

Other Side Effects

•         Diarrhea

•         Allergies

•         Candida albicans vaginal infections

•         Clostridium difficile large intestine infections (pseudomembranous colitis).

Suppression of Normal Microbiota

•         Beneficial bacteria colonize human body

•         Broad-spectrum antibiotics targets the infectious agent but also the normal microflora

Testing of antibiotic effectiveness Complication called superinfection

•         The treatment of bacterial infection is based on estimation which antibiotic is the most effective

•         If the case of bacterial resistance, the isolated strain should be tested against different antibiotics

The diffusion method

•         The surface of agar medium is uniformly inoculated with a test organism

•         The filter paper discs impregnated with different antibiotics

•         The effective antibiotic will inhibit the growth of bacteria - clear zone will occur.

•         The diameter of zone indicates the effectiveness of the antibiotic

Broth dilution test

•         Broth containing different antibiotic concentrations is inoculated with the test bacterium

•         A minimal concentration of antibiotic that prevents a visible bacterial growth is called minimal inhibitory concentration (MIC)

•         Minimal bactericidal concentration (MBC) is the minimal concentration of an antibiotic that kills bacteria (not only inhibits)

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