Chemotherapy (2)

Definition of ChemotherapyThe treatment of disease by means of

chemicals that have a specific toxic effect upon the disease-producing microorganisms or that selectively destroy cancerous tissue

DefinitionsCompounds that are used to kill or inhibit

growth of microbial organisms are called ANTIMICROBIALS

Substances produced by some plants or microorganisms that can kill or inhibit growth of other organisms are called ANTIBIOTICS

ANTIBACTERIALS refer to substances that act against bacteria

Modes of action of Antimicrobials

Bactericidal vs Bacteriostatic antibiotics

Antimicrobial targetsThe structures in microbes that are mainly

targeted by antimicrobials are Cell wallCell membraneCell proteinsCell nucleic acids

Basic structure of Bacterial cell wall

Therefore it is a N-G-N-G chains that are crosslinked together by peptaglycine bridges

Folic acid synthesis

ß-lactams & Glycopeptides (Vancomycin)

50 50 5030 30 30

DNA

mRNA

Ribosomes

PABA

DHFA

THFA

Cell wall synthesis

DNA gyrase

Quinolones

Protein synthesis inhibition

Protein synthesis inhibitionTetracyclines

Protein synthesis mistranslation

Macrolides & Lincomycins

DNA-directed RNA polymerase

Rifampin

Aminoglycosides

Sulfonamides

Trimethoprim

Inhibitors of cell wall synthesis Β-lactam bactericidal drugs;

Examples Penicillin

AmoxicillinAmpicillinCephalosporins

Vancomycin

Modes of action of cell wall inhibitorsΒ-lactam bactericidal drugsThey inhibit bacterial cell wall peptidoglycan

synthesis in growing bacteria. This leads to the death of the Bacteria

VancomycinThey kill Bacteria by interfering with

peptidoglycan polymerization (on gram positive bacteria only)

Inhibitors of RNA synthesisExample

Rifampicin

Mode of actionThey kill bacteria by inhibiting RNA polymerase

Commonly used in G+ve bacteria especially Mycobacterium tuberculosis

Inhibitors of DNA synthesisExamples

Fluoroquinolones

Polymixins (Polymixins B, colistin)

Sulphonamides

Inhibitors of protein synthesisProkaryotic and

eukaryotic ribosomes are structurally different

Eukaryotes (80s ribosomes) contain 60s and 40s subunits

Prokaryotes (70s ribosomes) contain 50s and 30s subunits

Inhibitors of protein synthesisExamples

AminoglycosidesTetracyclines PuromycinMacrolides

BACTERIAL RESISTANCE TO ANTIBIOTICS

BACTERIAL RESISTANCE TO ANTIBIOTICS

Antibiotic resistance is a type of drug resistance where a susceptible microorganism is able to survive exposure to an antibiotic

Human factors that predispose antibiotic resistance- Under dosage- Frequent use of antibiotics- Undirected use of antibiotics- making poor quality drugs and counterfeit drugs

Ability of Bacteria to express resistance to antibiotics

This basically happens due to structural and biochemical characteristics that can be due to - Inherent characteristics- Adaptive biochemical changes- Spontaneous genetics changes

Mechanisms of Bacterial resistance to antibiotics

Inherent structural mechanismsInherent biochemical mechanismsAdaptive biochemical mechanisms

Inherent antibiotic resistance genesGenetic mutations


Inherent structural mechanismSome bacteria have cell wall that prevents penetration of some bacteria

Example; Penicillin can not penetrate wall of G-ve bacteria because the wall has lipopolysaccharide layer that cover the site of peptidoglycan synthesis


Inherent Biochemical mechanismsInactivation of drugs – Some bacteria can

inactivate drugs by chemically modifying themExample; Staphilococcus produce β-lactamase enzyme which hydrolyses β-lactam ring of drugs like penicillin

Decreased drug accumulation – some bacteria have proteins that actively pump out antibioticsExample; S. aureus has enhanced fluoroquinolone pumping capability


Adaptive biochemical mechanismsAlteration of antibiotic target – Some

bacteria alter the stereochemistry of antibiotic targets hence antibiotic fails to bind

Example; Chloramphenicol action can be blocked by changes in bacterial 50s ribosomal unit that prevent it from binding


Inherent bacterial resistance genesBacteria store genetic information in genes

within chromosomal DNA. Bacteria has also other extrachromosomal DNA

called PLASMIDSOf the most important genes in the plasmids,

are the one with information on Antibiotic resistance

ANTIBACTERIAL RESISTANCE PLASMIDS (R-PLASMIDS)

They are collection of acquired foreign genetic elements that originated within other bacteria or fungi

R-plasmids are capable of combining with other plasmids, thus resistance to several antibiotics can reside on one plasmid

A bacterium may contain as many as 1,000 copies of a single plasmid

Bacteria are capable of transferring R-plamids from one cell to another through a process known as CONJUGATION

Transfer of resistance through genetic materials

This can happen in three ways

1.Conjugation

2.Transposons

3.Bacteriophages


Chromosaomal Genetic MutationsSpontaneous mutations in bacterial

chromosomes can lead to drug resistance

Basically chromosomal genetic mutations lead to the changes to structural or biochemical properties of a given bacteria and this can loose the susceptibility to a drug.

Selection of Antimicrobial agentsThis should consider four things;

Identity of the organism and susceptibility to a particular agent

The site of the infectionThe safety of the agent

Patient factors

Chemotherapeutic spectraThe chemotherapeutic spectrum of a particular

drug refers to the range of species of microorganisms affected by the drug

There are1.Narrow spectrum drugs, eg Isoniazid 2.Extended spectrum drugs, eg Ampicillin3.Broad spectrum drug, eg Tetracycline and

chloramphenicol

Combination of Antimicrobial drugs

Dynamics of combined antimicrobial action1.Indifference (2 + 3 = 3) 2.Antagonism (2 + 5 = 4) eg penicillin + tetracycline3.Synergism (2 + 2 = 5) eg Penicillin + Streptomycin

Dynamics of drug combination

ANTIBACTERIAL DRUGS

The following are the examples of the common Antibacterial groups

SULFONAMIDESMode of action – interferes FOLATE synthesis by

inhibiting dihydropteroate synthetase, that incorporates PABA in making folate

Spectrum of Action – BroadPreparations - Sulfamethazine

- Sulfadimethoxine- Sulfathiazole- Sulfachlorpyridazine- Sulfasoxasole and

sulfamethaxazole- Sulfacetamide- Sulfasalazine

Mode of action of Sulfonamides

FluoroquinolonesMode of Action – inhibit DNA replication. They

are bactericidalPreparation – Enrofloxacin

- Ciprofloxacin

Spectrum of activity - Broad

PenicillinsBelong to β-lactam bactricidal drugsMode of action – Inhibit cell wall synthesis

(bind transpeptidase enzyme involved in cross-linking of peptidoglycans)

Spectrum – act against G +ve aerobes and anaerobes

- Semisynthetic penicillins are effetcive against some G –ve bacteria

PenicillinsPreparations (Natural Penicillins)

– Penicillin G, Penicillin C- Penicillin V- Penicillinase-stable penicillins (methicillin, Oxacillin, cloxacillin,

dicloxacillin)Broad spectrum Penicillins

- Ampicillin, amoxicillin and Hetacillin - Carbenicillin and Ticarcillin- Azlocillin, mezlocillin and Piperacillin

Cephalosporins Modes of Action – Inhibit cell wall synthesis

(bactericidal)Preparations 1st Generation cephalosporins (G +ve aerobes)

- cephalexin, cefadroxil, cephaprin, cephalothin, cefazolin

2nd Generation cephalosporins (G +ve, plus some G –ve)- cefaclor, cefoxitin

3rd Generation cephalosporins (G +ve, G –ve, resistance to beta-lactamase, penetrate BBB)

- ceftiofur, moxalactam)

AminoglycosidesMode of action – Interferes protein syhthesis

(Bactericidal)PreparationsNatural – Streptomycin and

dihydrostreptomycin- Neomycin

Extended-spectrum - Gentamycin and amikacin- Tobramycin- Kanamycin

TetracyclinesMode of action – Inhibit Protein synthesis

(bond to 30s ribosome)Spectrum – BroadPreparations – Tetracycline

- Chlortetracycline- Oxytetracycline- Doxycycline

Chloramphenicol Mode of action - Bind to 50s of ribosome Spectrum – it is a broad-spectrum antibiotic,

and it is effective against most anaerobic bacteria

MacrolidesMode of action – Inhibit protein synthesis by

binding to 50s of ribosome

Spectrum – Effective against G +ve aerobes and anaerobes and Mycoplasma speices

Examples; - Erythromycin- Tylosin- Tilmicosin

LincosamidesMode of action – Bind to 50s of ribosome to

inhibit protein synthesis

Spectrum – effective against G +ve aerobes and anaerobes, Toxoplasma species, Mycoplasma species

Examples - Lincomycin- Clindamycin

Miscellaneous Anti-infectious agents

Metronidazole (Flagyl) – it disrupts DNA.- it is used in the treatment of bacterial

and protozoal infections (Amoeba, Giardia, Trichomonas)

Rifampicin – inhibits RNA synthesis- used in treatmet of Tuberculosis

Tiamulin – inhibits protein synthesisOthers – Bacitracin, Polymixin B.

ANTIVIRAL DRUGSTreatment of viral diseases is difficult because

- Viruses do not have many metabolic processes

- Viruses incorporate into the host cell and uses the host cell machinery for replication

- Most viruses undergo continuous spontaneous mutation, leading to the changing of structure

However there have been several drugs for viral infections with varying mechanisms and effectiveness

Mechanisms of action of antiviral drugs

Inhibition of Penetration to host cell - Amantidin – Inhibits uncoating

- Gammaglobulins – “neutralize” the virus


Inhibition of nucleic acidsInhibitors of viral DNA polymerase – Acyclovir, Vidarabine, Foscarnet

Interference with viral DNA synthesis – Gancyclovir, ribavirin

Inhibitors of Reverse transcriptase – Zidovudine, Zalcitabine, Didanosine


Neuramidase inhibitors - Zanamivir - Oseltamivir

Immunomodulators - Interferons - Pavilizumab - Imiquimod

Treatment of HIV and AIDS (ARVs)

Treatment of HIV and AIDS (ARVs)ARV Drugs Reverse transcriptase inhibitors Protease inhibitors Fusion inhibitors


Treatment of HIV and AIDS (ARVs)Protease Inhibitors



ANTIFUNGAL DRUGSGRISEOFULVIN Mode of action; It binds to microtubules to

inhibit spindle formation and mitosis. Fungistatic

KETOCONAZOLEMode of action; Inhibits synthesis of ergosterol

in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes

ANTIFUNGAL DRUGSAMPHOTERICIN BMode of action; Binds to ergosterol of cell

membranes and result to leakage of cell contents. Fungicidal.

FLUCYTOSINEMode of action; Inhibits thymidylate

synthetase, thereby inhibiting DNA and RNA synthesis

ANTIPROTOZOAL DRUGSAnticoccidial drugsAntitrypanosomal drugsAntitheilerial drugsAntibabesial drugsAnti-anaplasmal drugsAnti-Giardial drugs

Anticoccidial drugsAmprolium – block thiamine receptorsSulfonamides (s/methoxine, s/quinoxaline) –

Inhibit folate synthesisHalofuginone Sodium inophores (monensin, salinomycin,

lasalocid) – increase intracellular Na+ to impair Mit. functions

Decoquinate – inhibit DNA synthesisApronicid – interfere purine metabolism

Antitrypanosomal drugsHuman African Tripanosomosis (HAT)First stage drugs

- Pentamidine- Suramin

Second stage drugs- Melasoprol- Eflornithine

Antitrypanosomal drugsLivestock trypanosomosisDiminazene (Berenil®, Veriben®)

- bind to kinetoplast and nucleusPhenanthridinium compounds

(Isometamedium, Homidium)- inhibit DNA and RNA synthesis

SuraminMelarsomineQuinapyramine

Antitheilerial drugsHalofuginone – destroys parasitized

erythrocytesParvaquone – Interferes with electron

transport in mitochondriaBuparvaquone - Interferes with electron

transport in mitochondria

Antibabesial drugsImidocarb (Imizol®) – for therapeutic and

prophylaxis

Diminazine aceturate (Berenil®)

Antianaplasmal drugsTetracyclineImidocarbDithiosemicarbazones

Anti-Giardial drugsMetronidazole (Flagyl)Tinidazole (Fasigyn)Nitazoxanide

ANTIHELMINTHIC DRUGSThere are three major groups of helminths Nematodes (Antinematodal)Cestodes (Anticestodal)Trematodes (Antitrematodal drugs)

Health & Medicine

Chemotherapy (2)