Dr.Wafaa Ezz Elarab

Antimicrobial Drugs-1Antimicrobial Drugs-1

Modern era in Antibiotics begins with Fleming.

Chemicals used to treat microbial infections by

interfere with the growth m.o within host,

including (antibacterial, antiviral, antiparasitic

and antifungal) regardless of its origin.

AntibioticsAntibiotics

Are natural product produce by bacteria and

fungi which kill or inhibit the growth of other m.o

Antimicrobial DrugsAntimicrobial Drugs

Chemotherapy Chemotherapy Any chemical used in the treatment,

relief or prophylaxis of a disease.ProphylaxisProphylaxis

Use of a drug to prevent infection of a person (prevention of disease).

Antimicrobial Agents

• Disinfectant: •antimicrobial agent used only on inanimate objects

• Chemotherapeutic agent: •antimicrobial agent that can be used internally

• Bactericidal: •agent that kills bacteria

• Bacteriostatic: •agent that inhibits the growth of bacteria

Classification of Classification of antibiotics antibiotics ::

Antibiotics are classified several ways.1.1. On the basis of spectrum of activityOn the basis of spectrum of activity2.2. On the basis of the source On the basis of the source

3.3. On the basis of chemical natureOn the basis of chemical nature4.4. On the basis of mode of action On the basis of mode of action

1. According to the spectrum of 1. According to the spectrum of actionaction

Antibacterial drugs.

Antifungal drugs.

Antiviral drugs.

Antiprotozoal drugs.

Antihelminthic drugs.

2. According to the source 2. According to the source A. antibiotics produce by bacteria (bacitracin, polymixins and gramacidins)B. antibiotics produce by fungi (penicillins, cephalosporins and grisofulvin)C. antibiotics produce by actinomycetes(chloramphenicol, streptomycin, erythromycin and vancomycin.)Note: Most antibiotics are isolated from soil microorganisms

Microbial Microbial Sources of Sources of AntibioticsAntibiotics

3. According to chemical nature3. According to chemical nature

PeptidesPeptides

GlycopeptidesGlycopeptides

AminoglycosidesAminoglycosides

B-lactamsB-lactams

Macrolides Macrolides PolyenesPolyenes

4. According to mode of action4. According to mode of action

1.1. Inhibition of cell wall synthesisInhibition of cell wall synthesis2.2. Inhibition of nucleic acid synthesis, Inhibition of nucleic acid synthesis,

structure or functionstructure or function3.3. Inhibition of protein synthesisInhibition of protein synthesis4.4. Disruption of cell membrane structure or Disruption of cell membrane structure or

functionfunction5.5. Inhibit synthesis of essential metabolitesInhibit synthesis of essential metabolites

Features of Antimicrobial Drugs: Features of Antimicrobial Drugs: 1. Selective Toxicity1. Selective Toxicity

Cause greater harm to microorganisms than to host Chemotherapeutic index: lowest dose toxic to

patient divided by dose typically used for therapy

The larger the _______, the better the chemotherapeutic agent.

Ehrlich’s Magic Bullets

• 1906: PaulEhrlich discoveredSalvarsan 606

• 1930s: sulfa drugsdiscovered

Ehrlich developed the concept of specific toxicity

Chemotherapeutic spectraChemotherapeutic spectra• Narrow spectrum

– only against a single or a limited group of microorganisms,

• e.g. INH is active only against mycobacteria.

• Extended spectrum – against G+ organisms and also against a

significant number of G- bacteria • e.g., ampicillin

• Broad spectrum • e.g. tetracycline and chloramphenicol

– affect a wide variety of microbial species. – !!! alter the normal bacterial flora

• precipitate a superinfection of an organism, e.g., candida.

Features of Antimicrobial Drugs:Features of Antimicrobial Drugs:2. 2. Effects of Combining Drugs

Combinations are sometimes used to fight infectionsSynergistic: action of one drug enhances the activity of another or vice versa. e.g. 2 + 2 = 6)e.g. ampicillin+gentamicin in entercoccal carditisAntagonistic: activity of one drug interferes with the action of another. e.g. 2 + 2 < 4)

Features of Antimicrobial Drugs:Features of Antimicrobial Drugs:3. Adverse Effects3. Adverse Effects

1.1. Allergic ReactionsAllergic Reactions: some people develop hypersensitivities to antimicrobials

2.2. Toxic EffectsToxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects

3.3. Suppression of normal floraSuppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers

Features of Antimicrobial Drugs:Features of Antimicrobial Drugs:4. 4. Resistance to AntimicrobialsResistance to Antimicrobials

Some microorganisms inherently resistant to effects of a particular drug. (Intrinsic resistance)

Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes (more later). (Extrinsic resistance)

So, The Criteria of the Ideal Antimicrobial:So, The Criteria of the Ideal Antimicrobial:

Selectively toxic to microbe but nontoxic to host. Soluble in body- tissue distribution. Remains in body long enough to be effective -

resists excretion and breakdown. Does not lead to resistance. Cost not excessive. Hypoallergenic. Microbiocidal rather than microbiostatic.

Antibiotics Antibiotics : : Substance (such as penicillin) produce by

microorganisms that destroys or inhibits the growth of other pathogenic microorganisms and is used in the treatment of external or internal infections.Anti – againstBio – life

Mechanisms of action of Mechanisms of action of Antibacterial DrugsAntibacterial Drugs

1. - Inhibit cell wall synthesis2. - Inhibit protein synthesis3. - Inhibit nucleic acid synthesis4. - Injury to plasma membrane5. - Inhibit synthesis of essential

metabolites

Mechanisms of antibacterial action

1. Drugs that affect the bacterial cell wall1. Drugs that affect the bacterial cell wall

ß-lactam antibioticsß-lactam antibioticsPenicillins, cephalosporins and cephamycins, carbapenems and monobactams, ß-lactamase inhibitor/ß-lactam combinations

GlycopeptidesGlycopeptidesVancomycin

PolypeptidesPolypeptidesBacitracin

Drugs used for treatment of mycobacterial infectionsDrugs used for treatment of mycobacterial infectionsIsoniazid, ethinamide, ethambutol, cycloserine

1. Drugs that affect the bacterial cell 1. Drugs that affect the bacterial cell wallwall

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1. Drugs that affect the bacterial cell wall

Most bacterial cell walls contain a rigid girdle of peptidoglycan.

Penicillin and cephalosporin block synthesis of peptidoglycan, causing the cell wall to lyse.

Penicillins do not penetrate the outer membrane and are less effective against gram-negative bacteria.

Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria.

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Bacterial cell wall of G+ (A) and G- Bacterial cell wall of G+ (A) and G- (B) bacteria(B) bacteria

Historical aspect of Beta-lactam antibiotics:

1928 - Alexander Fleming observed the antibacterial effects of Penicillin

• 1940 - Florey and Chain extracted Penicillin

• Around the fungal colony is a clear zone where no bacteria are growing

• Zone of inhibition due to the diffusion of a substance with antibiotic properties from the fungus

Fleming and Penicillin

Basic mechanisms of antibiotic act on Basic mechanisms of antibiotic act on Lactam DrugsLactam Drugs

β-Lactam antibiotics are analogues of D-alanyl-D-alanine—the

terminal amino acid residues on the precursor NAM/NAG-

peptide subunits of the nascent peptidoglycan layer.

The structural similarity between β-lactam antibiotics and D-

alanyl-D-alanine facilitates their binding to the active site of

PBPs.

The β-lactam nucleus of the molecule irreversibly binds to the

PBP active site. This irreversible inhibition of the PBPs prevents

the final crosslinking (transpeptidation) of the nascent

peptidoglycan layer, disrupting cell wall synthesis

Penicillin and most other β-lactam antibiotics act by Penicillin and most other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell wallscatalyze cross-linking of bacterial cell walls.

Antibacterial Drugsthat InhibitCell Wall Synthesis

Mechanisms of resistanceMechanisms of resistance of of antibiotic act on antibiotic act on Lactam DrugsLactam Drugs

By definition, all β-lactam antibiotics have a β-lactam ring in their structure. The effectiveness of these antibiotics relies on their ability to reach the PBP intact and their ability to bind to the PBP. Hence, there are two main modes of bacterial resistance to β-lactams:1. Enzymatic hydrolysis of the β-lactam ring2. Possession of altered penicillin-binding proteins

Enzymatic hydrolysis of the β-lactam ring If the bacterium produces the enzyme β-lactamase or

the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.

The genes encoding these enzymes may be: inherently present inherently present on the bacterial chromosome  or may be acquired acquired via plasmid transfer (plasmid

mediated resistance), and β-lactamase gene expression may be induced induced by exposure to β-lactams.

Penicillinase (Penicillinase ( Lactamase Lactamase)

Figure 20.8

As a response to increased efficacy of β-lactams, some bacteria have changed the proteins to which β-lactam antibiotics bind. β-Lactams cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis. 

2. Possession of altered penicillin-binding proteins

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