Pharmacology Department

Topic : «Antibiotics – inhibitors of cell wall

synthesis and cell membrane function

Lecturer:
Associate Professor
Havrylyuk Iryna
 Antibiotics

 Antibiotics are compounds produced by bacteria and

fungi which are capable of killing or inhibiting competing
species

Nowadays the term is broadly used to refer to any

antibacterial substance produced naturally by
microorganisms, semisynthetic or fully synthetic that is
used to treat or prevent infections
 Discovery of
antibiotics

The first antibiotic

penicillin was
discovered by Alexander
Fleming, Professor of
Bacteriology at St.
Mary’s Hospital in
London in 1928
 Discovery of antibiotics

Fleming found that the mold Penicillium chrysogenum

secreted the substance that was capable of killing
staphylococci and other bacteria
Discovery of antibiotics

Ernst Chain and

Howard Florey at the
Sir William Dunn
School of Pathology
at Oxford University
succeded in purifying
the first penicillin,
penicillin G.
In 1940, Howard
Florey showed that
penicillin could
protect mice against
streptococcal
infection
Classification of antibiotics according to their
mechanism of action
Cell wall synthesis inhibitors
 Beta-lactams
 Glycopeptides
Inhibitors of cell membrane
function
 Polymyxins
 Daptomycin
Protein synthesis inhibitors
 Tetracyclines
 Aminoglycosides
 Macrolides
 Lincosamides
 Phenicols
 Oxazolidinones
 Streptogramins
Beta-lactam antibiotics
Mechanism of action of beta-lactam antibiotics
Mechanism of action of beta-lactam antibiotics

 beta-lactam antibiotics covalently bind to

penicillin-binding proteins (PBPs)
- PBPs are bacterial enzymes that catalyse
formation of cross-linkages between
peptidoglycan chain,
- PBPs also are involved in the maintenance
of the morphologic features of the bacteria
 Binding to PBPs  inhibit the
transpeptidation reaction (the last step of
bacterial cell wall synthesis)
 Cell lysis occurs either through osmotic
pressure or the activation of autolysins
 Are bactericidal
 Are effective against rapidly growing bacteria
that synthesize a peptidoglycan cell wall
 Resistance to beta-lactam antibiotics

 inactivation by beta-lactamases
- destroy the amide bond of the beta-lactam ring,
rendering the drug ineffective
- the information for beta-lactamase is encoded either in
chromosomes or in plazmids
- Substrate specificities of enzymes may be narrow
(penicillinases, cephalosporinases) or broad (ESBLs)
- Gram+ organisms secrete beta-lactamases extracellularly,
gram- into the periplasmic space
Modification of target PBPs
Impaired penetration of drug to target PBPs
Antibiotic efflux
Classification of beta-lactamases
 Penicillins
Natural penicillins
Penicillin G
Obtained from fermentations of the fungus Penicillium chrysogenum
Spectrum of action:
Gram+cocci (streptococcus pneumoniae, streptococcus pyogenes,
streptococcus viridans group)
Gram-cocci (Neisseria gonorrhoeae, Neisseria meningitidis)
Gram-positive bacilli (Bacillus anthracis, Corynebacterium
diphtheriae; anaerobic – Clostridium pefringens)
Spirochetes (Treponema pallidum, Treponema pertenue)

Disadvantages of penicillin G:
Unstable at acidic pH  parenteral administration only
Short duration of action  frequent administrations
Destroyed by beta-lactamases
Ineffective against gram-bacilli
 Penicillins

Natural penicillins

Penicillin V
More stable at acidic pH  oral administration

Long acting
Procaine penicillin – IM injection, 12-24 hours
Benzathine penicillin – IM injection, 2-3 weeks (beta-
hemolytic streptococcal pharyngitis, syphilis)
 Penicillins
Semisynthetic penicillins
Antistaphylococcal penicillins
Methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin
Indicated for infections caused by beta-lactamase-producing
staphylococci
Penicillin-susceptible streptococci and pneumococci are also
sensitive
In recent years increased rates of methicillin resistance in
staphylococci (MRSA)
Extended spectrum penicillins
Ampicillin, amoxicillin
Effective orally
Destroyed by beta-lactamases
Spectrum of action: gram+ cocci, gram- cocci, gram+ rods, some
gram- rods (E.coli, P.mirabilis, Salmonella, Shigella, H.influenzae)
Indications: respiratory infections, urinary infections, meningitis,
salmonella infections, prevention of bacterial endocarditis (in high risk
patients)
 Penicillins
Semisynthetic penicillins
Antipseudomonal penicillins
Carbenicillin, ticarcillin, mezlocillin, piperacillin
Available for parenteral administration only
Destroyed by beta-lactamases
Effective against many gram- rods, including Pseudomonas
aeruinosa
 Penicillins
Pharmacokinetics
Penicillins differ according to their stability to gastric acid
Stable to acid: penicillin V, dicloxacillin, ampicillin,
amoxicillin
Most incompletely absorbed after oral administration
Absorption is decreased by food  should be taken on
an empty stomach
Are widely distributed in the body
Penicillins are polar substances  low intracellular
concentrations
Poor penetration into the CNS (is increased when
meninges are inflamed)
Most of penicillins are eliminated by kidneys in
unchanged form; nafcillin and oxacillin are metabolized in
the liver
 Penicillins
Adverse effects
Hypersensitivity reactions
- 5% of paients develop
- cross-allergy to other beta-lactam antibiotics is
possible
GIT disorders: nausea, vomiting, diarrhea (due to
disruption of normal intestinal flora); pseudomembranous
colitis (Clostridium difficile)
Neurotoxicity: can provoke seizures if administered
intrathecally or if used in high doses (block GABA receptors
in the CNS)
Hematological disorders: bleeding and cytopenias
Nephritis (methicillin, nafcillin)
 Beta-lactamase inhibitors

Resemble beta-lactam molecules, but have very weak antibacterial

activity
They are potent inhibitors of many beta-lactamases (produced by
staphylococci, H influenzae, N gonorrhoeae, Salmonella, Schigella, E
coli, K pneumoniae – plazmid-encoded, produced by B fragilis, M
catarrhalis - chromosomal )
Protect penicillins and cephalosporins from inactivation by these
enzymes
Extend the spectrum of action of companion antibiotic
Are available only in fixed combinations with specific penicillins and
cephalosporins (amoxocillin+potassium clavulanate,
ampicillin+sulbactam sodium, piperacillin+tazobactam sodium)
 Cephalosporins
First-generation
Cefazolin, cefadroxil, cephalexin, cephalotin, cephapirin,
cephradine
They are very active against gram+ cocci (staphylococci,
streptococci, not MRSA) and some gram- rods Proteus
mirabilis, E coli, K pneumoniae
Are used in staphylococcal or streptococcal infections,
urinary tract infections, for surgical prophylaxis
 Cephalosporins
Second-generation
Cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil,
loracarbef, ceforanide, cefoxitin, cefotetan
They are active against organisms inhibited by first-
generation drugs with extended gram- coverage H
influenzae, Proteus mirabilis,, E coli, K pneumoniae,
cefotetan and cefoxitin - B fragilis
Are used in respiratory tract infections, mixed anaerobic
infections (peritonitis, diverticulitis, pelvic inflammatory
disease)
 Cephalosporins
Third-generation
Cefoperazone, cefotaxime, ceftazidime, ceftizoxime,
ceftriaxone, cefixime, cefpodoxime, proxetil, cefdinir, cefditoren,
pivoxil, ceftibuten, moxalactam
They have expanded Gram- coverage (Citrobacter, S
marcescens, Providencnta, beta-lactamase-producing H
influenzae and Neisseria, P aeruginosa - ceftazidime)
Destroyed by ESBLs
Cross blood-brain barrier
Cefotaxime and ceftriaxone are used for treatment of
meningitis (caused by pneumococci, meningococci, H
influenzae and susceptible enteric gram- rods); empirical
treatment of sepsis
Should be used with caution, as they are associated with
significant “collateral damage” (induction and spread of
antimicrobial resistance – ESBLs in Gram- bacteria, infection
with VRE, Clostridium difficile)
 Cephalosporins
Fourth-generation
Cefepime
More resistant to hydrolysis by chromosomal beta-
lactamases; hydrolysed by ESBLs
Broad spectrum of action
Good activity against P aeruginosa, Enterobacteriaceae,
MSSA, S pneumoniae, H influenzae and Neisseria sp
Cross blood-brain barrier
 Cephalosporins
Fifth-generation
Ceftaroline
Broad Gram+ and Gram- coverage
Unlike 1st-4th generation ceftaroline covers Listeria,
MRSA, Enterococcus faecalis, does not cover P
aeruginosa
Used for the treatment of skin and soft tissues infections
and community-acquired pneumonia; complicated
infections such as bacteremia, endocarditis, osteomyelitis
 Cephalosporins
Pharmacokinetics
Many drugs must be administered parenterally because
of their poor absorption
Available orally 1st generation – cefadroxil, cephalexin,
2nd – cefuroxime axetil, 3rd – cefdinir, cefixime, ceftibuten
Widely distributed in body fluids
Ceftriaxone and cefotaxime achieve high concentrations
in the CSF
Cefazolin penetrates bone
All cephalosporins cross placenta
Eliminated unchanged by kidneys
 Cephalosporins
Adverse effects
Hypersensitivity reactions; cross-sensitivity between
penicillins and cephalosporins (the highest for 1st
generation)
Nephrotoxicity
Hypoprothrombinemia with drugs containing
methylthiotetrazole group (cefoperazone, cefamandole,
cefotetan) is prevented by administration of vitamin K
Disulfiram-like effect (drugs containing
methylthiotetrazole)
Collateral damage
 Monobactams
Aztreonam
Spectrum of action: aerobic Gram- organisms (including
P aeruginosa); no activity against Gram+ bacteria and
anaerobes; gram- spectrum similar to that of the 3rd
generation cephalosporins
Stable to many beta-lactamases (not AmpC and ESBLs)
Penicillin-allergic patients tolerate aztreonam well
Elevates serum aminotransferases
Used to treat serious infections: pneumonia, miningitis,
sepsis caused by susceptible Gram- bacteria
 Carbapenems
Imipenem
Wide spectrum of action: most Gram- rods (including P
aeruginosa), Gram+ bacteria and anaerobes
Resistant to most beta-lactamases (not carbapenemases
or metallo-beta-lactamases)
Is inactivated by dehydropeptidase in renal tubules with
formation of nephrotoxic metabolite
Is combined with cilastatin (dehydropeptidase inhibitor)
Administered IV
Doripenem, meropenem
Have greater actiivity against Gram- aerobes and lower
activity against Gram+ bacteria
Ertapenem
Unlike other carbapenems has no activity against P
aeruginosa and Acinetobacter sp
 Carbapenems
Pharmacokinetics
Wide distribution in body fluids
Penetrate into CSF (except ertapenem)
Administered IV
Eliminated by kidneys
Clinical use
Treatment of mixed aerobic and anaerobic infections
Infections caused by susceptible organisms that are resistant
to other drugs
Infection caused by penicillin-nonsusceptible pneumococci
Serious infections caused by ESBLs-producing Gram-
bacteria
Adverse effects
Hypersensitivity reactions; cross-sensitivity to penicillins
Nausea, vomiting, diarrhea
Seizures (with imipenem)
 Glycopeptides
Vancomycin
Binds to D-Alanine D-Alanine terminus of the amino acid
peptide, inhibiting cross-linkage of the cell wall
Spectrum of action: Gram+ bacteria (staphylococci, including
MRSA, Enterococcus faecium, Enterococcus faecalis, C
difficile)
Poorly absorbed from GIT  for systemic effect administered
IV
Eliminated unchanged by kidneys
Indicated for life-threatening MRSA, methicillin resistant
Staphylococcus epidermidis, enterococcal infections (IV) and
antibiotic-associated C difficile colitis
Adverse effects:
Chills and fever
Nephrotoxicity
Ototoxicity
Red man syndrome (flushing due to release of histamine)
 Other cell wall synthesis inhibitors
Fosfomycin trometamol
Analog of phosphoenolpyruvate
Inhibits cytoplasmic enzyme enolpyruvate transferase 
↓ formation of UDP-N-acetylmuramic acid (the precursor of
N-acetylmuramic acid)
Spectrum of action: Gram+ and Gram- bacteria
Administered orally and parenterally
Eliminated unchanged by kidneys
Approved for use as a single 3-g dose for treatment of
uncomplicated lower urinary tract infections in women
Inhibitors of cell membrane
function

Lipopeptides

 Polymyxins

 Daptomycin
 Polymyxins
Mechanism of action
Bind to lipid A component of the lipopolysaccharide of the
outer membrane of Gram- bacteria  osmotic imbalance
 cell death
 Polymyxins

Spectrum of action: Gram- bacteria including P

aeruginosa, E coli, K pneumoniae, Acinetobacter sp,
Enterobacter sp
Poorly absorbed in the GIT
Polymyxin B is used parentrally and topically
Polymyxin E (colistin) administered IV or by inhalation
If used for systemic effect are associated with nephro-
and ototoxicity
Indicated for treatment of multiresistant infections
 Daptomycin
Mechanism of action
Binds to cell membrane via calcium dependent insertion
of its lipid tail  loss of cellular potassium (by pore
formation)  membrane depolarization  rapid cell death
 Daptomycin

Spectrum of action: Gram+ bacteria including

vancomycin-resistant enterococci and S aureus
Administered IV
Eliminated by kidneys
Indicated for cmplicated skin and soft tissue infections,
bacteremia and endocarditis
Pulmonary surfactant antagonizes daptomycin  should
not be used to treat pneumonia
Can cause myopathy  creatine phosphokinase levels
should be monitored
Thank you !!!