XI’AN JIAOTONG UNIVERSITY

Chemotherapeutic Drugs

Linrong
professor

Department of pharmacology
Email:linrong@mail.xjtu.edu.cn

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XI’AN JIAOTONG UNIVERSITY Chemotherapeutic Drugs
Chemotherapy is the drug treatment for the
diseases caused by bacteria and the other
pathologic microorganisms, parasites, and
tumor cells.

The objective of chemotherapy is to study and to

apply the drugs that have highly selective toxicity
to the pathogenic microorganisms in host body and
have no or less toxicity to the host, so as to prevent
and cure infective diseases caused by pathogens.
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 Antimicrobial Agents
XI’AN JIAOTONG UNIVERSITY

Linrong
professor

Department of pharmacology
Email:linrong@mail.xjtu.edu.cn

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 Definitions
• Chemotherapy is the drug treatment for the
diseases caused by bacteria and the other
pathologic microorganisms, parasites, and tumor
cells.
• The objective of chemotherapy is to study and to
apply the drugs that have highly selective toxicity
to the pathogenic microorganisms and have no
or less toxicity to the host.
• In most instances, the selective toxicity is relative,
rather than absolute.
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 Drug-pathogen-patient
• Selective toxicity- kills harmful microbes without
damaging the host
• Resistance- intrinsic versus acquired
• host defense -Immune response
• Pharmacokinetics- absorption, distribution,
metabolism, elimination
• Pharmacodynamics-adverse effects, dose-related,
allergy, idiosyncratic
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 What is the ideal antimicrobial drug ?
vHave highly selective toxicity to the pathogenic
microorganisms in host body
vHave no or less toxicity to the host.
vLow propensity for development of resistance.
vNot induce hypersensitivies in the host.
vHave rapid and extensive tissue distribution
vBe free of interactions with other drugs.
vBe relatively inexpensive

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 Definitions
• Antimicrobial drugs are chemotherapeutic drugs.
• Two categories:
– antibiotics Antimicrobial drugs produced by
microorganisms.
– synthetic drugs Antimicrobial drugs
synthesized in the lab.
• Antibacterial synthetic drugs
• Antifungal synthetic drugs
• Antiviral agents
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 What is an Antibiotic?
v“Antibiotic” is from antibiosis, meaning
against life.
vSubstances produced by various species
of microorganisms: bacteria, fungi,
actinomycetes — to kill or suppress the
growth of other microorganisms.
vToday the term antibiotic extends to include
synthetic antibacterial agents: sulfonamides
and quinolones.
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 Definitions
vChemotherapeutic Index (CI): the ratio of median
lethal dose (LD50) to median effective dose (ED50)
of infective animals.
LD50/ED50 or LD5/ ED95
Ø Generally the bigger the CI of a drug is, the lower its
toxicity, the better its curative effect and the greater
its value of clinical application.
Ø However, a drug with big CI does not mean that it is
definitely safety.
 Penicillin G has almost no toxicity and its CI is big, can
cause anaphylactic shock and lead to death. 9
 Definitions
vAntimicrobial spectrum : the scope that
a drug kills or suppresses the growth of
microorganisms.
ØNarrow-spectrum: The drugs that only act
on one kind or one strain of bacteria.
(isoniazid )
ØBroad-spectrum: The drugs that have a
wide antimicrobial scope. (tetracycline,
chloramphenicol )

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 Definitions
• Antimicrobial activity: the ability that a drug
kills or suppresses the growth of microorganisms.
• The minimal inhibitory concentration (MIC)
the minimum amount of a drug required to inhibit the
growth of bacteria in vitro.
• The minimal bactericidal concentration (MBC)
the minimum amount of a drug required to kill bacteria
in vitro.
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 Anti-Infective Agents
• History of Antibiotics
• Definition Chemotherapy, antibiotic, antimicrobial
drug , antimicrobial spectrum; broad-
spectrum, narrow-spectrum, antimicrobial
activity, Chemotherapeutic Index,
bacteriostatic, bactericidal.

• Mechanisms of antimicrobial agents

• Mechanisms of antibacterial resistance
• General principles of anti-infective therapy

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 Anti-Infective Agents
• History of Antibiotics
• Chemotherapy , antimicrobial drug

• Mechanisms of antimicrobial agents

A. Inhibition of cell wall synthesis
B. Inhibition of functions of cellular membrane
C. Inhibition of protein synthesis
D. Inhibition of nucleic acid synthesis
E. Inhibition of folic acid synthesis
F. Antiviral agents
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Mechanisms of antibacterial action

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Mechanisms of antimicrobial agents
• A. Inhibition of cell wall synthesis
– Penicillins and cephalosporins stop synthesis
of wall by preventing cross linking of
peptidoglycan units.
– Bacitracin and vancomycin also interfere
here.
– Excellent selective toxicity
Mechanisms of antimicrobial agents
• B. Inhibition of functions of cellular membrane
– The bacterial cell membrane is also called
cytoplasmic membrane. Its main compounds
are proteins and lipids.
– Polymyxins can selectively combine with
phosphatide in the cell membrane and cause
the increase of membranous permeability. As
the result, some important materials will outflow
from bacterial cells and result in death of bacteria.
 Mechanisms of antimicrobial agents
• C. Inhibition of protein synthesis
– Due to differences in ribosomes
– Eucaryotic cells have 80S (60S + 40S subunits)
ribosomes.
– Procaryotic cells have 70S (50S + 30S subunits)
ribosomes.
– Examples:
• Chloramphenicol,Macrolides and Clindamycin
bind to the 50S subunit.
• Tetracyclines and Aminoglycosides bind to
the 30S subunit.
Mechanisms of antimicrobial agents
• D. Inhibition of nucleic acid synthesis
– Stop DNA replication
• Example: Quinolones-inhibiting DNA
gyrase; Metronidazole???-DNA
polymerase
– Or stop RNA synthesis
• Example: Rifampin -binds to the bacterial
DNA-dependent RNA polymerase.
Mechanisms of antimicrobial agents
• E. Inhibition of folic acid synthesis
A drug mimics a normal metabolite and
acts as a competitive inhibitor.
– Enzyme of cell recognizes the drug instead of
the normal metabolite-Pathway stops.
– Example: Sulfonamides and trimethoprim are
similar to PABA (para aminobenzoic acid).
inhibit folic acid synthesis by blocking
dihydrofolic acid synthase and reductase
respectively.
 Anti-Infective Agents
• History of Antibiotics
• Definitions
• Mechanisms of antimicrobial agents
• Mechanisms of antibacterial resistance
Drug resistance
Types of resistance: Intrinsic or natural resistance
Acquired resistance
Mechanisms of antibacterial resistance

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 Resistance to antibacterial agents
• Drug resistance is the phenomenon that
susceptibility of pathogenic microorganisms
to drugs becomes lower or even loses after
the microorganisms contact with drugs many
times.
• When the bacteria show resistance to one
drug, they are also resistant to some other
drugs. This phenomenon is called cross
drug resistance.
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 Resistance to antibacterial agents
Types of resistance
• Intrinsic or natural resistance
• e.g., no target site in the bacteria
• Acquired resistance
– Resistance acquired by mutation is unusual,
– Resistance acquired by R-factors on plasmids is
common, very rapid method of acquiring
resistance that often involves resistance to
many antibiotics. (R factor contains genes
coding for enzymes that make the cell resistant to
antibiotics) 22
 Mechanisms of antibacterial resistance

① Produce enzymes that destroy the

chemical structures of drugs
② Change their cell membrane and cell
wall permeability to the drug
③ Develop an altered structural target
for the drug
④ Develop an altered metabolic pathway

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 Mechanisms of antibacterial resistance (1)

• Antibiotic inactivation
– bacteria acquire genes encoding
enzymes that inactivate antibiotics
• Examples include:
– β-lactamases
– aminoglycoside-modifying enzymes
– chloramphenicol acetyl transferase

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 Mechanisms of antibacterial resistance (2)

• Altered uptake of antibiotics, resulting

in:
– decreased permeability
– increased efflux
– For example, gram-negative bacillus can
induce some special proteins to block porin
channels in cell wall and prevent tetracyclines
into the bacillus.

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 Mechanisms of antibacterial resistance (3)

• Structurally modified antibiotic target site,

resulting in:

– For example, as the receptor protein on the 30s

ribosomal subunit may be deleted or altered as a
result of mutation, some aminoglycosides cannot
combine with the bacteria.

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 Mechanisms of antibacterial resistance (4)

• Develop an altered metabolic pathway

– Bacteria can develop an altered metabolic
pathway that bypasses the reaction inhibited
by drugs.
– For example, sulfonamide resistance my
occur as a result of mutations that cause
over-production of PABA or cause production
of a folic acid-synthesizing enzyme that has
low affinity for sulfonamides.
PABA, p-aminobenzoic acid
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 Mechanisms of antibacterial resistance

① Produce enzymes that destroy the

chemical structures of drugs
② Change their cell membrane and cell
wall permeability to the drug
③ Develop an altered structural target
for the drug
④ Develop an altered metabolic pathway

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Methods of avoiding resistance
• Avoiding the unnecessary use of antibiotics.
• Using antibiotics in full adequate dosage.
• If unnecessary, avoiding the topical use of
antibiotics for a prolonged period.
• Whenever possible, using the narrow-
spectrum antibiotics.
• If necessary, using a combination drug
regimen and using the drugs in turn.
 Anti-Infective Agents
• History of Antibiotics
• Definitions
• Mechanisms of antimicrobial agents
• Mechanisms of antibacterial resistance

• General principles of anti-infective

therapy

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General principles of anti-infective therapy

Selection of an appropriate anti-infective agent

① Identification of the infecting organism should
precede antimicrobial therapy when possible.
② The pathogenic microorganism susceptibility to
antimicrobial agents should be determined, if a
suitable test exists.
③ Factors that influence the choice of an anti-
infective agent or its dosage for a patient
include the age, renal and hepatic function,
pregnancy status, and the site of infection, etc.
 Antimicrobial combination therapy
Limit combination therapy to special situations
q Synergistic killing, e.g,β-lactam plus aminoglycoside for
endocarditis
q Mixed infections or severe infections of unknown cause,
e.g., limb infections in diabetic patients
q To prevent the emergence of resistance- M.tuberculosis
q Initial empiric therapy
Antimicrobial combination therapy
• Why not use 2 antibiotics all the time?
– Antagonism
– Cost
– Increased risk of side effects
– May actually enhance development of resistance
inducible resistance
– Interactions between drugs of different classes
– Often unnecessary for maximal efficacy
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