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Antibiotics, Antivirals
Antifungals and
Antimicrobial Resistance
Budiman Bela
T. Mirawati Sudiro
http://www3.niaid.nih.gov/topics/antimicrobialResistance/Understanding/drugResistanceDefinition.htm
Accessed March 23, 2009
Antibacterial Agents
Red azo dye protosil:
1935
protection of mice against systemic streptococcal infection
curative in patients suffering from the same infection
Cleavage result in release of p-aminobenzene sulfonamide
(sulfonilamide) that possess antibacterial activity 1st sulfa
drug
Compounds produced by microorganisms that
! inhibit the growth of other microorganism
(Antibiotic):
Alexander fleming: the mold Penicillium prevented the
multiplication of staphylococci
1940s: Streptomycin
1950s: Tetracyclines
Antibacterial Agent
New antibacterial agents have been
introduced and have to be continually
!
developed due to the remarkable ability of
bacteria to develop resistance to newly
introduced agents
Mode of action and target !
molecules of antibacterial agents
Inhibition of cell wall synthesis
Inhibition of nucleic acid synthesis
Inhibition of protein synthesis
Antimetabolites
Cell Wall Synthesis
-Beta-lactams
! DNA Replication
-Quinolones
!
-Vancomycin -Metronidazole
-Isoniazid
-Ethambutol
-Cycloserine
-Ethionamide
RNA Synthesis
-Rifampin
!
-Bacitracin -Rifabutin
-Polymyxin
DNA
Ribosomes
50 50 50
30 30 30
Protein synthesis
(50S ribosome)
!
Antimetabolites
-Sulfonamides
! -Chloramphenicol
-Dapsone -Macrolides
-Trimethoprim Protein synthesis -Clindamycin
-Para-aminosalicylic acid (30S ribosome)
! -Streptogramins
-Aminoglycosides
-Tetracyclines
-Oxazolidinone
Basic Mechanisms of Antibiotic Action
Antibiotic Action
Antibiotic Action
!
Inhibition of Nucleic Acid Synthesis !
Quinolone Binds subunit of DNA gyrase
Rifampin Prevents transcription by binding DNA-dependent RNA polymerase
Rifabutin Prevents transcription by binding DNA-dependent RNA polymerase
Metronidazole Disrupts bacteria DNA (is cytotoxic compound)
Antimetabolite
Sulfonamides
Dapsone
! Inhibit dihydropteroate synthase and disrupt folic acid synthesis
Inhibits dihydropteroate synthase
Trimethoprim Inhibits dihydrofolate reductase and disrupts folic acid synthesis !
Inhibition of Cell Wall Synthesis
Interference with bacterial cell wall
synthesis
The most common mechanism of antibiotic
-lactam antibiotics: !
Constitute the majority of cell wall-active
antibiotics
Penicilins, Chepalosporins, Cephamycins,
Carbapenems, Monobactams, -lactamase
inhibitors
Inhibition of Cell Wall Synthesis
Aminoglycosides:
Bactericidal:
Able to bind irreversibly to ribosomes
Penetration through the cytoplasmic membrane:
! Aerobic, energy dependent process
! Anaerobic bacteria are resistant to aminoglycosides
Streptococci and Enterococci:
! Cell wall of these bacteria can not be penetrated by
aminoglycosides
Treatment with aminoglycoside therefore requires an
inhibitor of cell wall synthesis (e.g. penicillin,
ampicillin, vancomycin)
Inhibition of Protein Synthesis
Oxazolidones !
Representative: Linezolid
Narrow-spectrum class of an antibiotics that block
initiation of protein synthesis by interfering with the
formation of the initiation complex at the 30S
ribosomal subunit cross-resistance with other
protein inhibitors does not occur can be used for
treatment of bacterial strains (Staphylococci,
streptococci and enterococci) that are resistant to
penicillins, vancomycin and the aminoglycosides
Inhibition of Protein Synthesis
Macrolides !
Bacteriostatic
Basic structure:
Macrocyclic lactone ring bound to two sugars
Reversible binding to the 50S ribosome blockage
of polypeptide elongation
Resistance:
Methylation of the 23S ribosomal RNA prevents binding by
the antibiotic
Destruction of the lactone ring by erythromycin esterase
Active efflux of the antibiotic from the bacterial cell
Inhibition of Nucleic Acid Synthesis
! Quinolones
Synthetic chemotherapeutic agents
Inhibition of enzymes required for DNA
replication, recombination and repair:
DNA gyrases or topoisomerases:
Resistance (chromosomally mediated), 2
mechanisms:
! Alteration of alfa subunit of DNA gyrase
Decreased drug uptake:
Changes in porin proteins on the bacterial surface
Biofilm !
Some bacteria Interact of with each other to form a sticky
web of bacteria and polysaccharides called a biofilm, which
adheres to a surface within a host (example: dental plaque,
on catether, pacemakers, intravenous devices, etc)
Bacteria in infectious biofilm tend to be 100x more drug
resistant to free bacteria caused by:
-Microbes are protected by the thick impenetrable nature of
extracellular matrix
- bacteria slow their growth and less active
- microbes communicate in mass regulation of certain
resistance mechanisme, e.g. drug pump.
INHIBITION OF VIRAL REPLICATION BY
ANTIVIRAL AGENTS
!
!
!
Ganciclovir:
- Aktif terhadap CMV !
- CMV tidak menyandi kinase timidin, tetapi dapat melakukan
fosforilasi GCV oleh suatu kinase protein yang disandi
oleh virus ini !
- Digunakan 30x lebih banyak oleh DNA polimerasa virus
dibanding oleh DNA polimerasa sel
- Digunakan dalam terapi antitumor dengan terapi gen
ANTI VIRUS TIPE LAIN
! AMANTADINE & RIMANTADINE
menghambat uncoating virus
virus Influenza A, profilaksis
FOSCARNET (Phosphonoformic acid = PFA)
menghambat DNA polimerase virus dan
reverse transcriptase
METHISAZONE
menghambat tahap akhir replikasi virus partikel
virus immature, non infeksius poxvirus
! OSELTAMIFIR (Tamiflu)
menghambat neuraminidasa virus influenza hambat
perakitan/budding
FUZEON
menghambat perlekatan GP41 HIV pada reseptor seluler
!
INTERFERON
!