lecture 7 chemotherapeutic agent

8/6/2019 Lecture 7 Chemotherapeutic Agent

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CHEMOTHERAPEUTIC

AGENTS

Dr. R. Tan



Chemotherapeutic Ag entsChemotherapeutic Ag ents

- are compounds that destroys pathogenic microorganism orinhibit their growth

- one of the most valuable method of treating infection- most common agents used are:

A ntibiotics

microbial products or their derivatives that are capable

of killing susceptible microorganism or inhibitingtheir growth



DESIRABLE PROPERTIES:

1. Selective toxicity- it must inhibit or destroy the pathogen without injury to the host

2. Bactericidal rather than bacteriostatic

3. One to which susceptible organisms do not becomegenetically or phenotypically resistant

4. Effective against a broad range of microorganism

5. Should not be allergenic; nor should continuedadministration of large doses cause adverse sideeffects

6.Remain active in the presence of plasma, body fluids, orexudates

7. Water soluble and stable; bactericidal level should berapidly reached and maintained for prolonged period

8. Cheap



ANTIBIOTICS ANTIBIOTICS

A re chemical substance produced by various species of microorganisms or to a similar substance produced wholly orpartially by chemical synthesis, which in low concentrationsinhibit the growth of other microorganisms

these substances functions to limit microbial growth by killingor inhibiting their growth

some are semi-synthetic in which the natural active component in the molecule is combined with a synthetic group

A ntibiotic producing organisms:

BacteriaBacillusStreptomyces

FungiPenicilliumCephalosporiumMicromonospora



� Mechanism of action:

1. Interfere with cell wall synthesis

2. Interfere with cell membrane function

3. Interfere with nucleic acid metabolism

4.Interfere with protein synthesis



Cell Wall InhibitorsCell Wall Inhibitors

A ny substance that destroys the cell wall or that preventsthe synthesis or incorporation of the wall polymers in

growing cells leading to the development of osmoticallysensitive cells and death

A gents with this mode of action are highly specific with lowtoxicity

Species of eubacteria that lacks a cell wall (ex. Mycoplasma)are not inhibited by these agents

A gents:

-lactam antibiotics Cycloserine Vancomycin Bacitracin



I. LACTAM ANTIBIOTICS

� Contain a unique 4 member -lactam ring� A gents: - Penicillin

- Cephalosphorins

- newer agents: Penems, Carbapenems

& Monobactams

� Bactericidal

� Penicillin-binding-protein (PBP)

- are enzymes that catalyze the last steps of peptidoglycanbiosynthesis

- Higher-molecular-weight PBP are the killing site for Lactam antibiotics

- Low-molecular-weight PBP are not essential for viability



Resistance to -lactam Antibiotic

A ttributed to 3 mechanisms:Inactivation of the drug

- the major basis for bacterial resistance to PCN

- Due to -lactamase = enzyme which split the -lactamring of PCN & Cephalosporin between the C &

N atoms to form inactive compounds

A lteration in the amount or affinity of the Penicillin-binding-proteins (target site)

Blocking of transport of drug into the cell- Gram (-) bacteria have a complex outer membrane that

retards the entry of -lactam antibiotic

- Most Gram (-) are resistant to Penicillin



PENICILLIN

� basic structure consist of thiazolidine ring joined to a-lactam ring which can be inactivated by -lactamase

� Penicillinase - specific type of -lactamase, showing

specificity for penicillins� PCN nucleus (6-aminopenicillamic acid) is the primary

structural requirement for biologic activity

� MO A : - affect bacteria by interfering with the normal

maintenance and synthesis of bacterial cell wall- inhibit the transpeptidation enzyme involve in

cell wall synthesis

� active against both gram (+) and gram (-) bacteria



Classifiication:

� Naturally occuring penicillins- Produced by culturing molds (Penicillium nonatum) and

collecting and purifying the penicillin

- Ex: Benzylpenicillin

Phenoxymethylpenicillin

� Semi-synthetic penicillins

- are produced by making chemical alterations in the

structure of a naturally occurring penicillin- Ex: Penicillinase-resistant Penicillin

Extended spectrum Penicillin

A nti-pseudomonal penicillin



Benzylpenicillin / Penicillin G

� Most useful

� administered parenterally (Penadur)

� Disadvantage:

- inactivated by acidic pH of gastric juice

- destroyed by Penicillinase

- hypersensitivity reactions

� DOC for Streptococcus pyogenes & S. pneumonia

� highly effective against most gram (+) andgram (-) cocci

� Least susceptible to some gram (+) cocci: enterococciand Penicillinase-producing S. aureus

Naturally occuring penicillins



Phenoxymethylpenicillin / Penicillin V

� A side chain variant of Pen G

� Has the same antimicrobial spectrum

� A dvantage: more stable in acid medium, thus better

gastrointestinal absorption

� can be given orally (Sumapen)



Penicillinase-resistant penicillins ± DOC for penicillinase-resistant organisms especially

S. aureus and S. epidermidis

± A n alteration of the side chain has provided protection

for the -lactam ring from the action of -lactamasewithout removing its antibacterial activity

± Includes:

- Methicillin and Nafcillin

- acid-labile, less active than penicillin G

- Isoxazolyl PCN (Oxacillin, Cloxacillin &Dicloxacillin)

- Combine resistance to -lactamase with resistance

to gastric acid

Semisynthetic Penicillin



Extended-spectrum penicillins

± The most striking change brought about by chemicalmanipulation of the penicillin side chain is an increaseof activity against gram negative organisms

± Ampicillin, Amoxicillin, Aminopenicillin- administered orally

- has a broad-spectrum of activity

- acid-stable but -lactamase sensitive

- highly active against gram (+) and gram (-)bacteria

(H. influenzae, E. coli, Proteus mirabilis, Salmonella& Shigella)



Anti-Pseudomanal penicillins

± Carboxypenicillins (Carbenicillin and Ticarcillin)

- both have broad spectrum activity

- active against gram (-) bacteria including Pseudomonas at the expense of diminishing activity against gram (+) org.

- More active against strains of Enterobacter, Serratia, andcertain strains of Proteus

- acid-stable

± Ureidopenicillins (Azlocillin, Mezlocillin, Piperacillin)

- More inhibitory to P. aeroginosa than carboxy derivatives

- Have activity against streptococci that is similar to A mpicillin



CEPHALOSPORINSCEPHALOSPORINS

- Produced from fungus Cephalosporium

- mechanism of action similar to penicillin in inhibiting thetranspeptidation reaction during peptidoglycan

synthesis- all these drugs are derivatives of cephem nucleus,

(7-amino-cephalosporamic acid) , lends itself tomodification which alters both microbiologic activity and

pharmacologic properties- contain a -lactam ring structure similar to penicillin

- inactivated by -lactamase



FirstGeneration

CephalothinCefazolinCephalexinCephaloridine

CephapirinCephadroxilCephradineCefacetrileCephaloglycinCephaloniumCefatrizineCefazaflur

- moderate-spectrum, active against penicillinase-producing, methicillin-susceptible staphylococci andstreptococci

- have activity against some gram (-) :E. coli, K . pneumoniae, and P. mirabilis

- no activity against B. fragilis,enterococci, methicillin-resistant staphylococci, Pseudomonas

Classification of Cephalosporins



SecondGeneration

CefaclorCefonicidCefprozilCefuroxime

CefuzonamCefmetazoleCefotetanCefoxitin

- greater Gram (-) spectrum whileretaining some activity against Gram(+)cocci- more resistant to beta-lactamase

with anti-anaerobe activity



Third

Generation

Cefotaxime

CeftriaxoneCeftizoximeCefmenoximeCefcapeneCefdaloximeCefdinir

CefditorenCefetamet CefiximeCefpodoxime

CefsulodinCefoperazoneCeftazidime

- broad spectrum of activity

- further increased activity against Gram (-) organisms while decreased activity forGram (+) organisms

- useful in treating hospital-acquiredinfections

- they can penetrate the CNS thus makingit useful in treating meningitis caused byS. pneumoniae, N. meningitidis,H. influenzae, and susceptible E. coli,

Klebsiella, and in the treatment of penicillin-resistant N. gonorrheae

Marked activity for Pseudomonas



FourthGeneration

CefepimeCefclidineCefluprenamCefoselisCefozopranCefpiromeCefquinome

- A re extended-spectrum agents withsimilar activity against Gram (+) org.as first-generation cephalosporins andGram (-)

- have a greater resistance to -lactamasesthan the third-generation cephalosporins

- Many can cross the blood-brain barrierand are effective in meningitis

- used against Pseudomonas aeruginosa



Other B-lactam antibiotics

± MO A

similar to penicillin ± have a -lactam ring and is resistant to -lactamase

a) Thienamycin

- are Carbapenem compounds that are stereochemicallydifferent from penicillin and cephalosporins

- Imipenem

a thienamycin in clinical use

active against all medically important organism includingorganism frequently resistant to other -lactam antibiotics

(S. aureus, S. faecalis, P. aeroginosa, Enterobacteriaceae,B. fragilis and -lactamase producing strains of H. influenzaeand N. gonorrheae)



b) Monobactam

- constitute a unique family of B lactams w/ a monocyclic nucleus- synthetic derivative: Aztreonam

- has excellent activity against aerobic gram (-)such as theEnterobacteriaceae, Pseudomonas, Gonococci and Hemophilus

c) B-lactamase inhibitors

- several B lactams have been developed that function asB-lactamase inhibitors

- such agents have little intrinsic antibacterial activity, but whencombined with a B-lactam, they protect the suceptible B-lactamfrom degradation and allow it to exert its lethal effect

- Clavulanic acid and Sulbactam - act synergically withamoxicillin, ampicillin, piperacillin, mezlocillin and

cefoperazone



II. CYCLOSERINE

- inhibit peptidoglycan synthesis

- the molecular basis for its bactericidal activity lies in itsstructural similarity with D-alanine

- broad-spectrum antibiotic used to treat patient with TB

- Its use is limited because it causes CNS toxicity; thus given forre-treatment of drug resistant cases, where it is administeredwith 3 or more drugs



III. VANCOM YCIN

- it interferes with peptidoglycan biosynthesis by binding rapidlyand irreversibly to the acyl-D-alanine terminus of amembrane bound peptidoglycan precursor

- narrow-spectrum, bactericidal antibiotic against many

gram (+) cocci- alternative drug in patient who are allergic to -lactam agents

- for serious infection caused by methicillin resistant S. aureus(MRS A )

- drug of choice for antibiotic-associated colitis caused by

C. difficile



IV. BACITRACIN

- is a polypeptide antibiotic produced by strain of Bacillus subtilis

- it inhibits peptidoglycan synthesis by preventing reentry

of lipid carrier into the reaction cycle- bactericidal for many gram (+) organism and

pathogenic Neisseria

- highly toxic: used for topical application only



Cell Membrane InhibitorsCell Membrane Inhibitors

Cell membrane� poses an osmotic barrier to free diffusion between the

internal and external environments� function:- it effects the concentration of metabolites and

nutrients within the cell- serves as a site for respiratory and certain

biosynthetic activities- certain antibiotics impair 1 or more of thesefunctions, resulting in major disturbancesin the viability of the cell

- agents: Polymixin Polyenes A zoles



. POLYMXIN

produced by Bacillus polymyxa

MO A : binds specifically to the outer surface of cell

membrane, altering their structure and osmoticproperties

members of this group are desinated by the letters

A , B, C, D, E but only Polymixin B and Polymixin E (colistin)are currently of clinical use

spectrum of activity is restricted to gram (-) organism

- reserved drug for the treatment of severe Pseudomonasinfection when organism is resistant to other antibiotics or

the patient is intolerant of the preferred drug



2. POLYENES

� are macrolide antibiotics, most important of which areantifungal agents

� MO A : binds to sterol in fungal membrane causing

disruption of membrane permeability resulting to

leakage of cell content � selectively inhibit organisms whose membrane contain

sterols (ergosterol)

� active against yeast, fungi and other eucaryotic cells but

inhibitory to procaryotic organism� Drug-induced resistance:

1. Decrease in the membrane ergosterol content

2. Modification of membrane sterols to one that bind lessefficiently to polyenes



Examples of Polyenes:

± A mphotericin B- cornerstone of antifungal therapy

- active agent most deep-seated fungi infection

- nephrotoxic and used only for serious life-threatening

infection ± Nystatin

- use to treat superficial or topical infections caused by

Candida



AZOLES Imidazoles

Triazoles� The difference between the imidazoles and the triazoles

involves the mechanism of inhibition of thecytochrome P450 enzyme - this

interrupts the conversion of lanosterol to ergosterol, acomponent of the fungal cell membrane

� The triazoles have been shown to have a higherspecificity for the cytochrome P450 than imidazoles,thereby making them more potent than the imidazoles



IMIDAZOLES

� Ketoconazole, Miconazole, Clotrimazole� are broad-spectrum antifungal agents active against yeast

dermatophytes and dimorphic fungi

� MO A : - acts by interfering ergosterol synthesis by the fungal cell

- disrupt fungal membrane permeability

- inhibit sterol synthesis

- Miconazole and Clotrimazole

- are limited to topical application only

- used as a treatment of cutaneous and vaginalcandidiasis

- Ketoconazole given orally, very effective for superficialand deep mycotic infection in human



TRIAZOLE

� Itraconazole, Fluconazole

� it is a lipophilic agent with broad spectrum of activityagainst yeast and dimorphic fungi

� MO A same with Imidazole

� better tolerated when given orally than the Imidazole

� effective in the treatment of dermatophytosis,chromomycosis, sporotricosis, and in some deep mycosesand opportunistic infection



Inhibitors of DNA FunctionInhibitors of DNA Function

� A ny agent that disturbs the structure of the organizeddouble helix of DN A is potentially capable of causing

profound effects on all phases of cell growth andmetabolism

� Mode of action inhibit cross linkage and intercalationbetween the stacked bases of the double helix DN A

� A gents:

± Quinolones

± Mitomycin

± Metronidazole

± Novobiocin



1. QUINOLONES

� all agents in the quinolone class are synthetic products

� it selectively and reversibly blocks DN A replication insusceptible organisms

� Examples: Nalidixic acid

NorfloxacinCiprofloxacin

� Nalidixic acid

- first to be introduced as derivative of naphthyridinecompound

- inhibit the subunit A of DN A gyrase and induce theformation of a relaxation complex analogue

- bactericidal

- for uncom licated UTI caused b ram - or anisms



� Norfloxacin

- most useful flourinated quinolone- 100x more active than Nalidixic acid

- spectrum of activity includes Enterococci,Staphylococci and Pseudomonas

- used to treat UTI

� Ciprofloxacin

- most potent of the quinolones

- active against most strains of gram (-) and gram (+)bacteria that cause urinary tract infection

- showed promising result with oral use in prophylacticselective decontamination of the intestine in a

neutropenic patient



2. MITOM YCIN

- converted enzymatically to a highly reactive hydroquinonederivatives that acts as a bifunctional alkalyting agent which acts on the guanine residues of DN A

- under certain condition blocks the synthesis of host cell DN A

- its toxicity prohibits its clinical use

3. METRONIDAZOLE

- effective antimicrobial agent for infection caused by

anaerobic bacteria and some protozoans- no effect on facultative and aerobic organism

- key feature of its microbial activity is the reduction of itsnitro group



4. NOVOBIOCIN

- bactericidal for a variety of bacteria, especially amonggram (+) bacteria

- primary inhibitory effect is on the replication of DN A

- target site is the subunit B component of the DN A gyrase,which inhibits the supercoiling of the DN A

- at present, there are no valid indication for thetherapeutic use of novobiocin



Inhibitors of Inhibitors of Protein SynthesisProtein Synthesis

and Assemblyand Assembly

- Protein synthesis is the end result of 2 major processes:- DN A -dependent RN A synthesis ( transcription)

- RN A -dependent protein synthesis (translation)

� Inhibitors of transcription� Inhibitors of translation

- Inhibitors of the 30s Ribosomal subunit

- Inhibitors of the 50s Ribosomal Subunit � Inhibitors of Protein A ssembly� Inhibitors of Tetrahydrofolate Synthesis (Folic acid synthesis)� Inhibitors of dihydrofolate reductase



Inhibitors of Transcription

� during transcription, the genetic information in DN A istransferred to a complementary sequence of RN A nucleotides by the RN A polymerase

� antibiotics alter the structure of the template DN A orinhibit the RN A polymerase will interfere with the

synthesis of RN A , and consequently with proteinsynthesis

� Actinomycin

- active against gram (+) and gram (-) bacteria

- toxic; with limited clinical use



� Rifampicin

- are ansa compounds which contain an aromatic ringsystem spanned by a long aliphatic bridge

- Rifampin

� most useful member of the group

� effective against gram (+) organism andmycobacteria

� major drug for the treatment of tuberculosis,leprosy & as prophylaxis against meningococcal meningitis



Inhibitors of translation

� translation of mRN A into protein are divided into 3 major phases:a) initiation : protein synthesis starts with the association of

mRN A , a 30s ribosomal subunit and formyl-methionyl-transfer RN A to form a 30s initiation complex

b) elongation- amino acids are added 1 at a time to a growing polypeptideon a sequence directed by mRN A

- this is the phase that is most susceptible to inhibition bya number of antibiotics

- ribosome is the target sitec) termination of polypeptide chain

- enzyme catalyzing peptide formation is peptidyl transferase(part of 50s subunit)

- termination is triggered when a chain termination signal(U AA , U A G or UG A ) is encountered at the site of the ribosome



Inhibitors of the 30s Ribosomal subunit

± Nitrofurans ± A minoglycoside ± Tetracycline

� NITROFURANS

- Nitrofurantoin- MO A : inhibit protein synthesis by blocking the initiation of

translation- used clinically to treat urinary tract infection especially

patient unable to tolerate Sulfonamides- good activity against gram (+) and gram (-) organisms- most active against E. coli, Klebsiella, Enterobacter and

S. faecalis- at present, it is recommended only for uncomplicated UTI



± AMINOGLYCOSIDE- includes: Streptomycin, Neomycin, Kanamycin, Tobramycin,

Gentamicin and A mikacin- MO A : binds to 30s ribosomal subunits and inhibit protein

synthesis- may irreversively block initiation of translation or cause mRN A

misreading or both

- toxic , poorly absorbed orally, poor penetration to CSF andrapidly excreted by the kidneys- can cause nephrotoxicity, ototoxicity , neuromuscular paralysis- Streptomycin

- bactericidal for gram (+), gram (-) bacteria and M tuberculosis

- drug of choice F. tularensis and Y . pestis infection- Gentamicin, Tobramycin and Amikacin

- active against gram (-) bacteria including Pseudomonas

- Neomycin- restricted to the pre-operative suppression of intestinal flora



3. TETRACYCLINES� are family of broad-spectrum antibiotics active against

gram (+) and gram (-) bacteria, Mycoplasma, Rickettsiaand Chlamydia

� 2nd to penicillins & Cephalosporins� inhibit protein synthesis by combining with the 30s subunits

of the ribosome� only bacteriostatic� Most undesirable side effect:

- superinfection secondary to incomplete oralabsorption inhibition of normal intestinal flora

- deposition of drug in calcified tissue stainingand impairment of structure of bones and teeth

� Bacteria develop drug resistance to tetracyclines bybecoming less permeable to the antibiotic



� includes the parent compound, Tetracycline, and several

natural products (Oxytetracycline, Chlortetracycline,Demethylchlotetracycline) and a number of syntheticderivatives

� Semi-synthetic: Doxycycline,M

inocycline- both are lipophilic and are absorbed completely in theGIT, thus less inhibitory for the normal gut flora

- lesser cases of resistance



Inhibitors of the 50s Ribosomal subunitErythromycin Chloramphenicol

Clindamycin and Lincomycin PuromycinFusidic acid

ERYTHROM YCIN� most important of the macrolide group, characterized by a

presence of a macrocyclic lactone ring� binds to the 50s ribosomal unit to inhibit peptide chain

elongation during protein synthesis� most frequently used antibiotic in patient allergic to penicillin� primarily bacteriostatic, but may be bactericidal for some

organism� effective against gram (+) bacteria and few gram (-) org.� treatment for Mycoplasma pneumonia, Legionella

pneumophila, diptheria and pertussis



CHLORAMPHENICOL� action is similar to erythromycin� bacteriostatic for gram (+) and gram (-) bacteria

including Rickettsia and Chlamydia� maybe inactivated by the enzyme chloramphenicol

acetyltransferase� its use demand caution because its very toxic, can cause

allergic & neurotoxic reaction� used only in serious and life-threatening situation� most common side effect is bone marrow depression leading

to aplastic anemia and decreased blood leukocytes� currently used in the treatment of H. influenza meningitis,

A naerobic infections and Typhoid Fever



� Clindamycin and Lincomycin- similar activity spectrum with Erythromycin but

chemically unrelated- active against group A streptococcus, Pneumococci and

Penicillinase producing staphylococci- Lincomycin

- Clindamycin- is the chloroderivative of lincomycin and is superior tothe parent compound in its activity and

absorption properties greater activity against anaerobic bacteria, esp.

B. fragilis infection as alternative to patients allergic topenicillin



� FUSIDIC ACID

- steroidal antibiotic with narrow antibacterial spectrum- active against gram (+) bacteria- no significant activity against gram (-) organism- Fucidin (salt of fusidic acid)

- used in the treatment of various seriousstaphylococcal infxn

� PUROM YCIN- not clinically useful but has an inhibiting effect on growth

of both procaryotic and eucaryotic organism



Inhibitors of the Protein Assembly

GRISEOFULVIN� a fungistatic agent specific for fungi whose cell wall

contains chitin� no effect on fungi with cellulose cell wall, on bacteria and

yeast protoplast � given orally� clinically useful in treating chronic dermatophyte infection ,

for which it is the standard therapy

after oral administration delivered on Stratum corneumvia the sweat or by deposition in

keratinocytes



Inhibitors of Tetrahydrofolate Synthesis

(Folic acid synthesis)

SULFONAMIDE

� generic name for derivatives of para-aminobenzene

sulfonamide or sulfanilamide� MO A : interfere with synthesis of folic acid (required for the

synthesis of purine & pyrimidine) precursor of RN A and DN A

� inhibitory activity against gram (+) and gram (-) organisms,

Nocardia, Chlamydia, and certain protozoa( Pneumocystis and Plasmodium)

� useful in the treatment of uncomplicated UTI caused byE. coli



Other analogues of Para-Aminobenzoic acid

Sulfones

± analogue of P A B A and is most useful clinically

± derivatives of the diaminodiphenylsulfone (dapsone)

± marked specificity against Mycobacteria

± primarily used to treat leprosy

Para-aminosalicylic Acid (PAS) ± highly specific for Mycobacterium tuberculosis

± used primarily as a second-line drug in the treatment

of tuberculosis



Inhibitors of dihydrofolate reductase

TRIMETHOPRIM� antifolic acid agent � very potent and a selective inhibitor of bacterial

dihydrofolate reductase

� spectrum of activity similar to sulfonamide , includinggram (+) cocci and gram (-) bacilli� are bactericidal and act synergistically with

sulfonamide sulfamethoxazole cotrimoxazol� useful in the treatment of recurrent or chronic UTI and

Pneumocystis infection� also effective against bronchitis, shigellosis andTyphoid fever



Other metabolite analogues

± Flucytosine- flourine analogue of cytosine (5-Flourocytosine)- an antifungal agent which is a true antimetabolite- effective against most systemic deep-seated fungal infection- drug of choice for Chromomycosis- toxic effect: skin rashes, diarrhea, liver damage and aplastic

anemia

± Isoniazid (INH)

- hydrazide of isonicotinic acid- highly specific for Mycobacterium tuberculosis- hepatotoxic- most potent anti-TB drug- never given as single drug

lecture 7 chemotherapeutic agent

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