SUBJECT:PHARMACEUTICAL MICROBIOLOGY

DATE :18/09/2019

MECHANISM OF ACTION OF ANTIBIOTICS

SUBMITTED BY,

RUBANYA A,

LS15171,V YEAR,

M.Sc LIFE SCIENCES,

BDU,TRICHY-24.
ANTIBIOTICS

 Chemical substances produced by the microorganisms that

inhibits the growth or kills the micro organisms.
 An antibiotic is a selective poison.
 It has been chosen so that it will kill the desired bacteria, but not
the cells in your body. Each different type of antibiotic affects
different bacteria in different ways.
 For example, an antibiotic might inhibit a bacteria's ability to turn
glucose into energy, or the bacteria's ability to construct its cell
wall. Therefore the bacteria dies instead of reproducing.

MECHANISM OF ACTION

 The mechanism of action is the biochemical way in which a drug is

pharmacologically effective. This can be a specific target where
the drug binds like an enzyme, as is the case with many
antibiotics, or a receptor. Mechanism of action describes the
biochemical process specifically at a molecular level.

 Different antibiotics have different modes of action, owing to the

nature of their structure and degree of affinity to certain target
sites within bacterial cells.

 Some of the antibiotics perform their action as,

 1) Inhibitors of cell wall synthesis

 2) Inhibitors of cell membrane function

 3) Inhibitors of protein synthesis

 4) Inhibitors of nucleic acid synthesis

 5) Inhibitors of other metabolic processes
A. INHIBITORS OF CELL WALL SYNTHESIS

1. Penicillins

2. Cephalosporins

3. Other antibacterial agents that act on cell walls

B. DISRUPTERS OF CELL MEMBRANES

1. Polymyxins

2. Tyrocidins

C. INHIBITORS OF PROTEIN SYNTHESIS

1. Aminoglycosides

2. Tetracyclines

3. Chloramphenicol

4. Other antibacterial agents that affect protein synthesis

a. Macrolides

b. Lincosamides

D. INHIBITORS OF NUCLEIC ACID SYNTHESIS

1. Rifampin

2. Quinolones

E. ANTIMETABOLITES AND OTHER ANTIBACTERIAL AGENTS

1. Sulfonamides

2. Isoniazid

3. Ethambutol

4. Nitrofurans
INHIBITION OF CELL WALL SYNTHESIS

The cellular contents in bacteria are surrounded by an inner peptidoglycan cell

wall in addition to an inner plasma membrane. Gram-negative bacteria also have
an additional outer lipid bilayer.

Specific antibiotics interfere with the synthesis of the cell wall, weakening the
peptidoglycan scaffold within the bacterial wall, compromising the structural
integrity. Since mammalian cells have a plasma membrane but lack the
peptidoglycan wall structure, this class of antibiotics selectively targets the
bacteria with no significant negative effect on the cells of the mammalian host.

Several transpeptidases and transglycosylases connect the newly formed

peptidoglycan structures to the cell wall peptidoglycan matrix. ß-Lactam
antibiotics (example Penicillin), with their structural similarity to the D-alanyl-D-
alanine group within the peptidoglycan structure, compete for the binding sites of
transpeptidases and prevent the assembly of the peptidoglycan layer in both
Gram-positive and Gram-negative bacteria.

Vancomycin, a glycopeptide antibiotic with a significantly larger structure than

Penicillin, also prevents cell wall construction by interfering with
transglycosylases. Its effectiveness is limited to Gram-positive bacteria because its
large size prevents its penetration to the outer cytoplasmic membrane of Gram-
negative bacteria

Examples: penicllins,

cephalosporins,

bacitracin and

vancomycin

EX-PENICILLINS
  Penicillins contain a b-lactam ring which inhibits the formation of
peptidoglycan crosslinks in bacterial cell walls (especially in Gram-
possitive organisms)
 Penicillins are bactericidal but can act only on dividing cells
 They are not toxic to animal cells.

· Synthesis of Penicillin

· b-Lactams produced by fungi, some ascomycetes, and several actinomycete

bacteria

· b-Lactams are synthesized from amino acids valine and cysteine

· Resistance

· This is the result of production of b-lactamase enzyme in the bacteria

which destroys the b-lactam ring

· It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and

Neisseria gonorrhoea

· Adverse effects

· Allergy : Patient should be always asked about a history of previous

exposure and adverse effects

· Superinfections (e.g.caused by Candida )

· Diarrhoea : especially with ampicillin, less common with amoxycillin

· Rare: haemolysis, nephritis

INHIBITORS OF CELL MEMBRANE FUNCTION

Cell membranes are important barriers that segregate and regulate the intra-
and extracellular flow of substances. A disruption or damage to this structure
could result in leakage of important solutes essential for the cell’s survival.
Because this structure is found in both eukaryotic and prokaryotic cells, the action
of this class of antibiotic are often poorly selective and can often be toxic for
systemic use in the mammalian host. Most clinical usage is therefore limited to
topical applications.

Examples: polymixin B and colistin.

INHIBITORS OF PROTEIN SYNTHESIS

Enzymes and cellular structures are primarily made of proteins. Protein synthesis
is an essential process necessary for the multiplication and survival of all bacterial
cells. Several types of antibacterial agents target bacterial protein synthesis by
binding to either the 30S or 50S subunits of the intracellular ribosomes.

This activity then results in the disruption of the normal cellular metabolism of
the bacteria, and consequently leads to the death of the organism or the
inhibition of its growth and multiplication.

 Need to affect bacteria, not mitochondria

 Aminoglycosides (streptomycin, gentamicin) change shape of 30S
ribosome subunit
 Tetracycline blocks access to A site of 30S subunit
 Chloramphenicol block peptide bond formation from 50S subunit
 Macrolides (erythromycin) block 50S subunit action
 Antisense NAs bind to beginning of mRNA and block translation

Examples: Aminoglycosides, macrolides, lincosamides, streptogramins,

chloramphenicol, tetracyclines.
EX-CHLORAMPHENICOL

 This inhibits bacterial protein synthesis.

 It is well absorbed and widely distributed , including to the CNS.
 It is metabolized by glucoronidation in the liver.
 Although an effective broad-spectrum antibiotics, its uses are limited
by its serious toxicity.
 The major indication is to treat bacterial meningitis caused by
Haemophilus influenzae, or to Neisseria menigitidis or if organism is
unknown.It is also specially used for Rikettsia (typhus).

ADVERSE EFFECTS

 A rare anemia, probably immunological in origin but often fatal

 Reversible bone marrow depression caused by its effect on protein
synthesis in humans
 Liver enzyme inhibition

INHIBITORS OF NUCLEIC ACID SYNTHESIS

DNA and RNA are keys to the replication of all living forms, including bacteria.
Some antibiotics work by binding to components involved in the process of DNA
or RNA synthesis, which causes interference of the normal cellular processes
which will ultimately compromise bacterial multiplication and survival.

Examples: quinolones, metronidazole, and rifampin

EX-QUINOLONES (bactericidal)
nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin,
sparfloxacin

Mode of action - These antimicrobials bind to the A subunit of DNA gyrase

(topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA
synthesis.

Spectrum of activity - Gram-positive cocci and urinary tract infections

Resistance - Common for nalidixic acid; developing for ciprofloxacin

 The quinolones are effective but expensive antibiotics.

 With increased use, resistance to these drugs is becoming more
common.

Examples and clinical pharmacokinetics

Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for
lower urinary tract infections, as it has no systemic antibacterial effect.

 Ciprofloxacin is a fluoroquinolone with a broad spectrum against

Gram-negative bacilli and Pseudomonas,
  It can be given orally or i.v. to treat a wide range of infections,
including respiratory and urinary tract infections as well as more
serious infections, such Salmonella.
 Activity against anaerobic organism is poor and it should not be first
choice for respiratory tract infections.

Adverse effects

 Gastrointestinal upsets
 Fluoroquinolones may block the inhibitory neurotransmitter, and this
may cause confusion in the elderly and lower the fitting threshold.
 Allergy and anaphylaxis

INHIBITORS OF OTHER METABOLIC PROCESSES

Other antibiotics act on selected cellular processes essential for the survival of the
bacterial pathogens. For example, both sulfonamides and trimethoprim disrupt
the folic acid pathway, which is a necessary step for bacteria to produce
precursors important for DNA synthesis. Sulfonamides target and bind to
dihydropteroate synthase, trimethophrim inhibit dihydrofolate reductase; both
of these enzymes are essential for the production of folic acid, a vitamin
synthesized by bacteria, but not humans.
EX-SULFONAMIDES AND TRIMETHOPRIM

Sulfonamides are rarely used alone today.

Trimethoprim is not chemically related but is considered here because their

modes of action are complementary.

Mode of action - These antimicrobials are analogues of para-aminobenzoic

acid and competitively inhibit formation of dihydropteroic acid.

Spectrum of activity - Broad range activity against gram-positive and gram-

negative bacteria; used primarily in urinary tract and Nocardia infections.

Resistance - Common

Combination therapy - The sulfonamides are used in combination with

trimethoprim; this combination blocks two distinct steps in folic acid
metabolism and prevents the emergence of resistant strains.

ADVERSE EFFECTS

 Gastrointestinal upsets
 Less common but more serious:sulfonamides: allergy, rash, fever,
renal toxicity,Trimethoprim: anemia, thrombocytopenia
 cotrimoxazole: aplastic anemia
REFERENCES

Hugo and Russell’s Pharmaceutical Microbiology

https://www.researchgate.net/publication/317381477_Antibiotics_Mode_of_action_and_mechanisms_
of_resistance

Pharmaceutical microbiology-1st edition-elsevier

https://www.researchgate.net/publication/317381477_Antibiotics_Mode_of_action_and_mechanisms_
of_resistance