Antimicrobial Agents

(General Considerations)

Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow
dixitkumarrakesh@gmail.com
 Objectives
• After this lecture you will be able to answer
– What are antimicrobials, antibiotics,
chemotherapeutic agents (Terminologies used in
antimicrobial treatment)
– Classification of antimicrobials
• Chemicals
• Mechanism
• Spectrum

– Mechanisms of action of antimicrobials

– Resistance development in antimicrobials
– Multidrug resistant microorganisms
A naturopath tells
“One should never take antibiotics
Except in
Pneumonia, a kidney infection, boils, meningitis,
encephalitis, osteomyelitis, occular infections, or
other serious
illness………………………………………………….”
 Allopath is Lucky to have the help of Antimicrobials

But This Luck may not last long due to reasons……

– Inappropriate use,… Overuse…..
– Antimicrobial resistance
– Reduced immunity and worsening of environment
– patients having co morbid illnesses like diabetes,
malnutrition………………..
– Less interest of pharmaceuticals in this field
– Costly new antimicrobials
Antimicrobials , Antimicrobials , Antimicrobials ,
Antimicrobials, Antimicrobials , Antimicrobials
Antimicrobials!!!
Penicillin, ampicillin, amoxycillin, ticarcillin, piperacillin,
flucloxacillin, dicloxacillin, oxacillin, methicillin, nafcillin,
carbenicillin, eryhtromycin, clindamycin, roxythromycin
clarithromycin, tetracycline, doxycycline, minocycline,
vancomycin, teicoplanin, augmentin, gentamicin, tobramycin,
amikacin, streptomycin, azithromycin, aztreonam, cephalexin,
cefotaxime, cephamandole, cefepime, ceftriaxone,
ceftazidime, cefpirome, imipenem, chloramphenicol,
cotrimoxazole, ciprofloxacin, norfloxacin, trimethoprim,…….
………………………………………………………………………………………………
………………………………………………….. hundreds of different
antimicrobial agents on the market.
 Terminology
Chemotherapy –
 Use of drugs to treat infections and malignancy. (Antimicrobials and
Antineoplastic agents)
Pharmacodynamic agents-
 Drugs regulating physiological process of body and act on the body cells.
Chemotherapeutic agents-
 Selectively acting against microbes or malignant cells. (Don’t touch body
cells)
Antimicrobials –
 Used in treating infectious diseases.
Antibiotics –
 Produced from microbes to inhibit or kill other microbes. (Antimicrobials from
microbes)

All antibiotics are antimicrobials but all antimicrobials are not

antibiotics 6
 Bacteriostatic-
 Stop the growth of bacteria
 Bactericidal-
 Kill the bacteria
 PAE-
 Post antibiotic effect
 Minimum Inhibitory Concentration (MIC)-
 Which stops the growth
 Minimum Bactericidal Concentration (MBC)-
 Which kills by 99.99%

(Bactericidal -less value of MBC-MIC,

Bacteriostatic - more value of MBC-MIC)
• Prebiotics-
– Stimulate the growth of intestinal commensals and
prevent multiplication and establishment of pathogenic
bacteria.
– Lactulose, Lactitol, Inulin
• Probiotics-
– Live microbial substances used as supplements to
maintain or improve the intestinal bacterial flora.
– Lactobacilli and Bifidobacteria
 Gram positive & Gram Negative
• Gram positive bacteria have
– thick cell wall
– Peptidoglycan directly accessible from environment
• Gram negative bacteria have
– Thin cell wall
– Surrounded by inner and outer membrane
– Of lipopolysaccharide, phospholipids, and proteins
– Outer membrane is a barrier to diffusion of antibiotics
• Limited antibiotics may diffuse through porins
 Historical Perspectives
• Chenopodium-
– for intestinal worms
• Mouldy curd –
– for boils
• Chaulmoogra oil-
– for Leprosy
• Mercury –
– for Syphilis
• Cinchona Bark-
– for Malaria
 Historical perspectives
• Pasteur- (1877)
– Phenomenon of antibiosis
• Paul Ehrlich- (1906)
– Father of Chemotherapy, Coined term chemotherapy
• Domagk- (1935)
– Discovery of sulfonamides (Prontosil to sulphanilamide)
• Fleming, Chain, Florey-
– Penicillin (1929, 39, 41) from penicillium
• Waksman-
– Streptomycin, from actinomycetes,
– Coined term antibiotic
 Introduction of Class of antimicrobial agents (SPECTM)
• 1935 - Sulphonamides
• 1941 - Penicillins
• 1944 - Aminoglycosides
• 1945 - Cephalosporins
• 1949 - Chloramphenicol
• 1950 - Tetracyclines
• 1952 - Macrolides
• 1956 - Glycopeptides
• 1957 - Rifamycins
• 1959 - Nitroimidazoles
• 1962 - Quinolones
• 1968 - Trimethoprim
• 2000 - Oxazolidinones
• 2003 - Lipopeptides
 Antimicrobial Classification
• Chemical structure
• Mechanism of Action
• Organism type
• Spectrum of activity
• Static or Cidal
• Origin of antimicrobials
 Chemical Classification (Public Loves GOOD Quality BATSMAN)
• Polypeptides- Polymyxin, Colistin, Bacitracin
• Poyene antibiotics- Nystatin, Amphotericin-B, Hamycin
• Lincosamide- Lincomycin, Clindamycin
• Glycopeptides- Vancomycin, Teicoplanin
• Oxazolidinone- Linezolid
• Others-----------------Riampicin, Griseofulvin, etc
• Diaminopyrimidines- Trimethoprim, Pyrimethamine
• Quinolones- Nalidixic acid, ciprofloxacin
• Beta-lactam- Penicillins, Cephalosporins, Monobactams, Carbapenems
• Aminoglycosides- Streptomycin, Gentamycin
• Tetracyclines- Oxytetracycline, Doxycycline
• Sulphonamides- Sulfadiazine, Sulfamethoxazole,
• Macrolides- Erythromycin, Clarithromycin
• Azoles- Fluconazole, Clotrimazole
• Nitroimidazoles- Metronidazole, Tinidazole
• Nicotinic acid derivatives- Isoniazide, Pyrizinamide, Ethionamide
• Nitrobenzene derivaties- Chloramphenicol
• Nitrofuran derivatives- Nitrofurantoin, Furazolidone
Organism affected Sources
• • Fungi-
Anti-viral
– Penicillin
• Anti-bacterial – Cephalosporins
– Griseofulvin
• Anti-fungal
• Bacteria-
• Anti-protozoal – Polymyxin B
• Anthelmintic – Colistin
– Bacitracin
• Actinomycetes-
– Most common
– Aminoglycosides,
Tetracyclines,
Chloramphenicol
– Macrolides
Spectrum Bacteristatic
– Sulfonamides and Trimethoprim
• Narrow – Tetracyclines
– Penicillin G – Macrolides (Erythromycin)
– Streptomycin – Chloramphenicol
– Erythromycin – Ethambutol
– Nitrofurantoin
• Broad
– Tetracycline
– Chloramphenicol Bactericidal
– Cotrimoxazol
• Extended – Penicillins
– Ampicillin – Cephalosporins
– Amoxicillin – Aminoglycosides
– Most…….. – Vancomycin, Daptomycin
– Fluroquinolones (ciprofloxacin)
– INH, Rifampicin, Pyrazinamide
– Polymixins, Bacitracin
 Spectrum
(Narrow, Broad, Extended)
 Mechanism of action
• Cell Wall synthesis inhibition-
– Beta-lactams, Vancomycin, Cycloserines
• Cell membrane Leakage-
– Polypeptides, Polyenes
• Folate Synthesis inhibition-
– Sulfonamides, Pyrimethamine, Cotrimaxazole, PAS, Ethambutol

• DNA gyrase and Topoisomerase inhibition-

– Fluroquinolones
• RNA polymerase inhibition-
– Rifampicin,,
• Protein Synthesis Inhibition- (ATT)
– Aminoglycosides, tetracyclines, Chloramphenicol, Macrolides,
 Differences between human cells Vs Bacterial Cells
(Makes the antibacterial selective)
• Human cells don’t posses wall 1
– (Peptidoglycans = peptides + sugar)
• Human cell membrane is different 2
– ( Bacteria Contain Hypanoids in place of Sterol)
• Human cells take preformed dihydrofolic acid
3
– (no need of PABA in human)
• Dihydrofolic acid reducatase enzyme is different 4
– (thousand time affinity)
• Topoisomerase II are different
5
– (in bacteria IV, DNA Gyrase)
• DNA dependent RNA polymerase is different 6
• Ribosome 60S subunit (in bacteria 50S) 7
• Ribosome 40S subunit (in bacteria 30S)
8
 Cell Wall

Beta Lactams
 Protein Synthesis
Chloramphenicol-
Macrolides-
Erythromycin, Azithromycin
etc.

Aminoglycosides.
Gentamicin, Amikacin,
etc.
• DNA gyrase (Gyrase) belongs to DNA
topo-isomerases
• DNA gyrase, referred to simply as gyrase,
• DNA gyrase also known as DNA
topoisomerase IV (In bacteria).
• In human Topoisomerase II
Quinolones
PABA Sulphonamides (PABA analogue and inhibitor of DHFAS)
Dihydro-folic acid Synthetase
Dihydrofolic acid
Dihydro-folic acid reductase Trimethoprim and Pyrimethamine (inhibitor of
Tetrahydrofolic acid DHFAR)

Purines and Pyrimidines

DNA And RNA
Quinolones
DNA unwinding (DNA gyrase) (Inhibitor of DNA gyrase and Topoisomerase IV)
DNA multiplication
Threads sepeartion (Topoisomerase IV)

DNA dependent RNA Polymerase Rifampicin

(inhibitor of DNA dependant RNA Polymerase)
Ribosome unit (50S) Chloramphenicol, Macrolides (50S)
mRNA Protein Synthesis
Ribosome unit (30S)Aminoglycosides, Tetracyclines (30S)
tRNA + Amino Acids
PABA Sulphonamides (PABA analogue and inhibitor of DHFAS)
Dihydro-folic acid Synthetase 3
Dihydrofolic acid
Dihydro-folic acid reductase Trimethoprim and Pyrimethamine (inhibitor of
Tetrahydrofolic acid 4 DHFAR)

Purines and Pyrimidines

DNA And RNA
Quinolones
DNA unwinding (DNA gyrase) (Inhibitor of DNA gyrase and Topoisomerase IV)
5
Threads sepeartion (Topoisomerase IV)

RNA Polymerase 6 Rifampicin (inhibitor of DNA dependant RNA Polymerase)

7
Ribosome unit (50S) Chloramphenicol, Macrolides (50S)
mRNA Protein Synthesis
Ribosome unit (30S)
8 Aminoglycosides, Tetracyclines (30S)
tRNA + Amino Acids
Cell Wall synthesis inhibition-
1
Beta-lactams, Vancomycin, Cycloserines
Cell membrane Leakage-
Polypeptides, Polyenes 2

PABA Sulphonamides (PABA analogue and inhibitor of DHFAS)

Dihydro-folic acid Synthetase 3
Dihydrofolic acid
Dihydro-folic acid reductase
Tetrahydrofolic acid
4 Trimethoprim and Pyrimethamine (inhibitor of DHFAR)

Purines and Pyrimidines

DNA And RNA
DNA unwinding (DNA gyrase) 5 Quinolones
(Inhibitor of DNA gyrase and Topoisomerase IV)
DNA multiplication
Threads sepeartion (Topoisomerase IV)
6 Rifampicin (inhibitor of RNA Polymerase)
RNA Polymerase
Ribosome unit (50S)
7 Chloramphenicol, Macrolides (50S)
mRNA Protein Synthesis
tRNA + Amino Acids Ribosome unit (30S) Aminoglycosides, Tetracyclines (30S)
8
 3
2 4 5

1 8
 ANTIBIOTICS
Dose-dependent (With PAE) Time-dependent

Antibacterial effect directly Effectiveness depends on a

depends on their concentrations period of time, during which
in the locus of infection concentration in blood
(high doses 1-2 times/24h) overwhelms MIC for a particular
causative agent
(constant i.v. infusion or 3-6
times/24h)
•Aminoglycosides
•Beta-lactames
•Fluoroqinolones
•Glycopeptides
•Metronidazol
•Macrolides
•Amphotericin B
•Tetracyclines
•Vancomycin
 Post-Antibiotic Effect
• The capacity to inhibit the growth of bacteria
after removal of the drug from the culture
(body)

• Provides additional time for the immune

system to remove bacteria that might have
survived antibiotic treatment before they can
eventually regrow after removal of the drug.
• Cell mebrane
– Polypeptides and Polyenes
1
– Polymyxin, Colistin, Bacitracin, Nystatin, Amphotericin-B, Hamycin
• Cell Wall synthesis by acting on cross linking
2
– Penicillins, Cephalosporins, Monobactams, Carbapenems, Vancomycin, Teicoplanin,
• Cell wall synthesis by acting on inhibition of mycolic acid (Long Fatty acid present in
mycobacterial family)
– Isoniazide, Pyrizinamide, Ethambutol
2
• Interfering with folic acid metabolism
– Sulphonamides- Sulfamethoxazole, Sulfadoxine,
3 Antibacterial - Co-trimoxazole

•
– Diaminopyrimidines- Trimethoprim, Pyrimethamine
4 Antimalarial- Co-trimazine
DNA gyrase and topoisomerase IV inhibitors
5
– Quinolones- Nalidixic acid, ciprofloxacin, Ofloxacin, Pfloxacin, Gatifloxacin, Sparfloxacin
• Inhibition of DNA dependeant RNA Polymerase
– Rifampicin, 6
• Acting on 50S ribosome
7
– Macrolides- Erythromycin, Clarithromycin, Azithromycin, Roxithromycin,
– Chloramphenicol, Lincomycin, Clindamycin, Linezolid
• Acting on 30 S ribosome
– Aminoglycosides- Streptomycin, Gentamycin, Kanamycin, Amikacin, Tobramycin
– Tetracyclines- Oxytetracycline, Doxycycline 8
 Mechanisms Of Resistance
Resistance
Intrinsic Acquired
Not Dangerous/ Dangerous/
less clinical importance clinical importance

Mutation Transferred

Conjugation
Transformation
Transduction
 Inherent Resistance
(Not Much of clinical importance)

• Bacteria naturally resistant

– e.g., Gram-negative bacteria resistant to penicillins
– Genes transferred to the bacterial progeny.

• Bacteria may be resistant because

– No mechanism to transport the drug into the cell.
– Do not contain antibiotic’s target process or protein.
 Acquired Resistance
• Due to exposure of antimicrobials
• Horizontal evolution:
– Resistance genes pass from resistant to
nonresistant strain,
– Antibiotics- a selective pressure.
– Gene transfer mechanisms:
• Conjugation.
• Transduction.
• Transformation.
 Cellular Resistance

•
• ATTACK OF THE SUPERBUGS:
ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly.
Jan 07
 Mechanisms of Resistance
• Enzyme-based resistance–
– Break down of antimicrobials.
• Ribosomal modifications–
– Methylation of ribosome interferes with antibiotic binding.
• Protein modifications–
– Mutations leave target protein unrecognizable to antibiotic
• Metabolic resistance–
– Overcome competitive inhibition by alternate pathway.
• Efflux–
– Pumps antimicrobials out.
Resistance to Antibiotics
 Resistance in some antibiotics
• Beta-lactams: - Hydrolysis , mutant PBP
• Tetracycline: - Active efflux from the cell
• Aminoglycosides- Inactivation by enzymes
• Sulfonamides- Alternate pathway,
• Fluoroquinolones- Mutant DNA gyrase
• Chloramphenicol- Reduced uptake into cell
• Macrolides - RNA methylation, drug efflux
 Factors favoring Resistance
•Prescription related factors:
• Overuse
• Early discontinuation
• Over continuation
• Less dose, duration
•Livestock doping:
• Animals exposure
 Superbugs
(Microorganisms with multiple resistance)
• MRSA - Methicillin-resistant Staphylococcus aureus
• VISA - Vancomycin intermediate resistant Staphylococcі
• VRE - Vancomycin-resistant enterococci
• ESBLs - Extended-spectrum beta-lactamases
(microorganisms – resistant to cephalosporins and
monobactams)
• PRSP - Penicillin-resistant Streptococcus pneumoniae
• MRPA (MDR-PA)- Multidrug resistant Pseudomonas
aeruginosa
• MRAB (MDR-AB) - Multidrug resistant Acinetobacter
baumannii
 Why worry?
n MDRO are dangerous
– Difficult to treat
– More virulent
– Increase mortality and morbidity
n Resource-intensive
– More expensive and toxic antibiotics
– Increase length of hospitalization
– Increase demand for isolation-facilities
Thanks