CHEMOTHERAPEUTIC AGENTS (ANTIMICROBIAL resistance.

; standard reference for the determination of

DRUGS) antibiotic resistance; this was based on US.

- Chemical used to treat diseases German Domagk

- Arsenic (Salvaran)
- He discovered Sulfanilamide (1932); known as
- Ex: Antimicrobial drugs/agents
Prontosil
*kills chemotherapeutic agents in vivo (inside
 1st antimicrobial agent (synthetic);
the body of individuals); in vitro (in the lab)
commercially available compared to
3 Types of Antimicrobial Drugs Penicillin.
 A form of sulfonamide drug
o Antibiotic – naturally produced by bacteria,
fungi etc. ; major chemotherapeutic agents; CAN BE USE FOR:
some could be used in treatment of cancer
 Children’s antibacterial drugs
diseases.
 Hepatitis C antibacterial
o Semi-synthetic – antibiotic that are chemically
 Anticonvulsants
altered in the lab.
 Anti-diabetic agents
o Synthetic - walang halong natural (did in the
 Antiretrovirals (HIV)
lab)
 Diuretics
 Ex: Sulfanilamide (Synthetic)
 Dermatological
Paul Ehrlich
Selman Waksman
- German scientist/chemist
- Soil-dwelling bacteria (streptomyces) as source
- Proposed the term “chemotherapy” (the use of
of antimicrobial agents
chemical to selectively kill a pathogen by having
- “antibiotics” – AA that are naturally produced
little or no effect on person.
by microbes, bacteria, or fungi; refers to those
- Chemotherapeutic agents is like “magic bullets”
antimicrobial drugs that can either inhibit or kill
(they can specifically locate a pathogen to kill,
bacteria (only bacteria) other terms like
that’s why they don’t have effects on the
antiprotozoan, antiviral, antifungal.
host/or little effect)
- Scientific name of Soil microbe: Streptomyces
**Treponema pallidum – C.A of Syphilis (Salvarsan) griseus (is an actinomycin)
- Specific antibiotic of streptomyces:
*Selective Toxicity – a drug or the agent should be
STREPTOMYCIN (there are still a lot of
toxic to the pathogen only and not the host.
infections that being used of streptomycin)
- arsenic compound against trypanosome parasites
Dr. Abelardo Aguilar
and syphilis
- A Filipino physician who discovered soil samples
Alexander Fleming
that were later developed into Erythromycin
- In 1929, he discovered Penicillin (antibiotic (gastro-resistant tablets), which is an antibiotic
produced by penicillium chrysogenum (fungus) compatible with those allergic to penicillin.
before was penicillium notatum); example of - Can treat respiratory tract infection like
natural antimicrobial agent or antibiotic. bronchitis, pneumonia
- Penicillin – has the ability to kill or to inhibit - Beta lactam: penicillin and cefuroxime
bacteria. (antibiotics that specifically target the cell wall
of the pathogen)
**Zone of Inhibition (ZOI) – an area of media where - Can also treat tonsilitis, STD (syphilis, AIDS –
bacteria are unable to grow, due to the presence of caused by VIRUS)
a drug that impedes their growth.
*the specificity of erythromycin is BACTERIA only.
indicates that compound has antibiotic property. If
there’s no ZOI or can’t produce ZOI, it is not *Karamihan ng bacteria ngayon ay resistant na ng
effective na antimicrobial agent.; we can measure ERYTHROMYCIN.
the diameter of ZOI; pag mataas ang diameter, mas
SOURCES
effective yung antimicrobial agent. ; through ZOI,
we can determine if resistant na ba ang mga  Natural – naturally produced by microbes
microbes or hindi. (bacteria, fungi)
 Semi-synthetic – chemically modified
Ex: amoxicillin – more than 8ml diameter yung ZOI,
antibiotics; increase toxicity of natural
it means SUSCEPTIBLE ang mga microbes.
antimicrobial agents.
- Less than 8ml of diameter, it means RESISTANT.  Synthetic – make entirely in the lab
Ex: *Quinolones
**magkakakaiba ang standard ng measurement sa pag *Sulfonamide drugs
determine ng resistance.
Sources of Some Common Antibiotics and semi
**CLSI (Clinical Laboratory Standard Institute)– manual synthetics
book; use this if you want to learn more about the
 Microorganism Antimicrobial **Not all antibiotic have the same storage condition
FUNGI (need to consider)
o Penicillium Penicillin
Chrysogenum *0 degree Celsius – it is freezing already that is use
o Penicillium Griseofulvin for long term storage.
griseofulvum  Remain in specific tissues in the body long
o Acremonium spp. Cephalotin
enough to be effective
BACTERIA
o Amycolatopsis Vancomycin : Antibiotic- they remain specific tissue in the body
orientalis long enough to be effective, not just temporarily.
o Amycolaptosis Rifampin
rifamycinica  Kill the pathogens before they mutate and
o Bacillus Bacitracin become resistant to it.
licheniformis
Mechanisms of action of microbial drugs
o Bacillun polymyxa Polymyxin
Gentamicin (broad (Listed are representative drugs for each type of action)
o Micromonospora
purpurea spectrum antibiotic, it
can be used to treat  INHIBITION OF CELL WALL SYNTHESIS
infectious caused by o Penicillin – specific mode of action
gram (+) and (-) o Cephalosporins- specific mode of action
bacteria) ; they target the enzyme na gumagawa
oPseudomonas ng tetrapeptide cross bridge (pag
fluorescens Mupirocin masira mawawala ang integrity ng cell
o Saccharopolyspora wall ng microbes.
erythraea Erythromycin
o Vancomycin
o Streptomyces o Bacitracin
griseus Streptomycin
o Isoniazid
o Streptomyces
Neomycin o Ethambutol
fradiae
o Echinocandins (antifungal)
o Streptomyces
Tetracycline  Targets formation of peptidoglycan in the cell
aureofaciens
o Streptomyces wall
Chloramphenicol *beta lactam – active compound of antibiotics
venezuelae
o Streptomyces (penicillin and cephalosporins); ang ginagawa
Amphotericin B niya ay tinataget niya yung enzymes na nakiki
nodosus
o Streptomyces cross linked ng peptidoglycan. (structure: sugar
Ivermectin
avermitilis backbone (alternating NAG and NAM) and
*This genus was formerly called Cephalosporium. peptides)
**tetrapeptides: amino acids
*You are allergic to antibiotic if you get rashes, chest
 Targets the peptide chains in the peptidoglycan.
tightening
*target the tetrapeptide chain not the enzyme.
Allelopathy – a microbe killing another microbe through *VANCOMYCIN – sinira ang cell wall ng pathogen
the production of antibiotic. (tetrapeptide cross bridge)
 Block the transport of NAG and NAM
- Negative form of
*NAG and NAM – was made inside the bacterial
Properties of Antimicrobial Drug cell since they are sugars. They need to
synthesize and later connect (dugtong-dugtong)
 Kill or inhibit the growth of pathogens by to form ng sugar backbone
interfering with important process in pathogen.  Targets the mycolic acid
Ex: cell wall synthesis (inhibit the formation of **MA can be found in the acid fast bacteria
cell wall in pathogen), DNA, cell membrane (their bacteria are not affected by these
 Cause no damage to the host only to the antibiotic (isoniazid and ethambutol); they can
pathogen. use this by treating TB (mycobacterium
- Selective toxicity tuberculosis – acid fast bacteria)
 Cause no allergic reaction in the host  Targets the glucan portion of the cell wall
*Antimicrobial drug – should be cause no allergic *for Fungi cells
reaction in the host; sometimes this property didn’t *not taken orally but superficially (skin);
achieved because there are some humans that are ointment
allergic to antibiotic. *AZOLE – mostly antifungal to the therapeutic
options for treatment of systemic
 Stable when stored in solid or liquid form
 INHIBITION OF PROTEIN SYNTHESIS
*Optimum – perfect storage condition of the
o Aminoglycosides
temperature of antibiotic. (0-10-25 degree Celsius,
o Tetracyclines
room temperature)
o Chloramphenicol
o Macrolides
 o Antisense nucleic acids membrane of fungi by binding to ergosterol;
 Targets the 30S subunit of ribosomes humans are not affected to amphotericin B
30S- small subunit because we don’t have ergosterol in our cell
*some aminoglycosides (streptomycin targets membrane.
the protein synthesis and walang pakialam sa  Inhibits synthesis of ergosterol
cell wall ng pathogen) target the 30S cause  Destroys the outer membrane of Gram (-)
change in 30S shape, so MRNA is misread; bacteria
translation couldn’t proceed  Disrupts membrane transport
*70S RIBOSOMES – PROKARYOTES  Changing the permeability of cell membranes in
- walang pakialam ang antibiotic sa atin bc they only parasitic worms
target those 70s ribosomes. Since we don’t have it we
are not affected.  INHIBITION OF GENERAL METABOLIC
*80S RIBOSOMES – EUKARYOTES PATHWAY (especially in the formation of FOLIC
ACID)
 Targets the 50S subunit of ribosomes o Sulfonamides
50S – larger subunit o Trimethoprim – targets the enzyme;
*antibiotics that targets 50S: Macrolides change the structure of enzyme so it
(applied on the surface of skin not orally) and won’t fit into the PABA.
chloramphenicol (prevents the formation of o Dapsone - targets the enzyme; change
peptide bonds upon forming amino acids (hindi the structure of enzyme so it won’t fit
mabuo ang amino acids) into the PABA.
*Peptide bond – the bond that connects the  By acting as structural analog of para-
amino acids in a protein. (20 AA – e dugtong2 aminobenzoic acid (PABA)
to make a protein)  By binding to the enzyme where PABA binds
 Prevents the binding of TRNA to the 50S subunit  Other antimetabolites:
of the ribosome *Atovaquone
 Targets the TRNA *Heavy metals
 Binds to the MRNA *Blocks the activation of viruses
*Tetracycline **FOLIC ACID – essential metabolite in the production
*since the Tetracycline and some in nucleotides. Why needs nucleotides? Because w/o it
aminoglycosides block the docking site of TRNA there is no nucleic acids; without FA hindi magagawa
hindi na makakabalik si TRNA so binding of ang nucleotides.
TRNA will result to the release of AA para 2 TYPES OF NUCLEOTIDES
madugtong sya doon sa growing polypeptide 1. Purines
chain ng AA. 2. Pyrimidines
**isa sa mga ginagamit ng method ng mga **NUCLEIC ACIDS – series/polymer of
pathogen para maging INFECTIVE sila is through the nucleotides
production of ENZYMES (hyaluronidase, **NUCLEOTIDES – composed of sugar,
collagenase, etc.) phosphate groups, nitrogen base (ADENINE,
**Proteins are important in microbes and human GUANINE, CYTOSINE, THYMINE) = AT, GC
- Structural component of cell (peripheral **DNA -double helix that is made of
proteins on the surface of the cell membrane); complementary pair of nucleotides.
for transport (channel or carrier proteins) PABA – important in the production of folic acid.
substances that could not cross the *Structural analog – structurally similar (konting
phospholipid bilayer (sugar) sugar can’t be able pinagkaibahan)
to pass through bc they have big molecules they *PABA – important metabolite for the production of
need proteins to pass through to the cell purines and pyrimidines nucleotides.
- For communication and to maintain integrity ; it leads to the production of Dihydrofloric acid.
of the cell; *Antimetabolite – they prevent the production of the
- *enzymes are proteins important metabolite.
Sulfanilamide, sulfamethoxazole, sulfisoxazole = FULL
 DISTRUPTION OF CYTOPLASMIC MEMBRANE SYNTHETIC ANTIMICROBIAL AGENT; inunahan nila si
-destroy the Cell membrane PABA sa enzymes.
o Polymyxins Antiviral drugs = Amantidine and Rimantidine (similar
o Polyenes (antifungal subs.) action with structural analog and prevent uncoating
 Attaches to ergosterol in the cell membrane of viral particles; prevent the fusion of lysosome and
fungi phagolysosome containing the virus.)
*Ergosterol – important component in the cell *Lysosome – if ma encounter ng virus si lysosome, the
wall of the fungi ; important bc they regulate lysosome will cause the virus uncoat the genetic
the fluidity of the membrane. material
*Hopanoids – bacteria Vesicle – phagosome (containing virus)
*Amphotericin B – polymerase; antifungal Phagolysosome – if the phagosome fuses with a
medications used for fungal infections and lysosome it will become phagolysosome.
leishmaniasis; create a hole in the cell
  INHIBITION OF DNA OR RNA SYNTHESIS Broad-Spectrum vs. Narrow-Spectrum Antibodies
o Actinomycin  Broad-Spectrum Antibodies
o Nucleotide analogs – they act as an - Antibiotics that work against many different
to prevent the action of DNA kinds of pathogens.
polymerase. Ex: Isoniazid (mycobacteria), and polymyxins
o Quinolones - (gram negative bacteria)
o Rifampin  Narrow-Spectrum Antibiotics
 Binding to DNA thereby blocking DNA - Antibiotics that work against only few kinds of
replication and RNA synthesis pthogens
 Acting as nucleotides/nucleoside analogs Ex: Tobramycin, streptomycin, (mycobacteria)
*lipid polymerase can stop the formation of penicillins (gram negative, positive and
DNA chlamydias), sulfonamides, cephalosporins,
 Inhibits DNA gyrase (gram negative and positive) and tetracycline
- Also known as topoisomerase (Gram -, +, chlamydia’s and rickettsia’s)
- We don’t have this, only bacteria  Antibacterial drugs primarily affect prokaryotic
- In order for the DNA to be replicated it needs to cells but not eukaryotic cell.
be uncoil to be able to use in DNA replication.  Antibiotics work better if prepared in
- - many lipid that blocked the DNA gyrase so it combination such as:
can’t uncoil the DNA therefore it can’t be us as - Co-trimoxazole (trimethoprim and
a template to make a new DNA strand. sulfamethoxazole)
 Inhibits the action of RNA polymerase - Co-amoxiclav (amoxicillin and clavulanate)
-prevent the formation of MRNA. If there’s no - Quad tabs (RIPE: Rifampin, Isoniazid,
MRNA, there will be no protein synthesis. Pyrazinamide, Ethambutol)
 Reverse transcriptase inhibitors (enzyme)
*Synergism – combination of antibiotic to become
- for viruses
effective.
- the genetic material of retroviruses is RNA it
needs to be converted into DNA before it can Side Effects of Chemotherapeutic Agents:
be used by the host cell.
1. The microorganisms may mutate and become
- the enzyme that converted the RNA back to
resistant to the antibiotic.
DNA of retrovirus is called RT.
- To prevent development of drug-resistant strain
- if the RT is inhibited the RNA can’t be
and superinfection
converted back to DNA, so it can’t survive sa
host cell. **in the development of antimicrobial resistance it
*TRANSCRIPTION – will lead to the production of a is not the antimicrobial drug that creates the AR but
MRNA. rather they create pressure of the environment
*DNA POLYMERASE – DNA replication making the other groups of pathogens to become
*RNA POLYMERASE – for the production of MRNA resistant. Meaning pag present dyan yung agent na
iyon they could eliminate those by
Antiviral Agent: leaving resistance rooms to survive)
1. Azidothymidine (AZT) or Zidovudine
- Acts as analog to nucleoside thymidine *Dark one is drug-resistant mutant
- *not yet nucleotide bc it doesn’t have *light one – drug-sensitive cells
phosphate group.
2. Thymidine – nucleoside form of thymine. **resistant gene can be found in the chromosome
of pathogen or in the plasmid.
 INHIBITION OF PATHOGEN’S ATTACHMENT TO, R plasmid – genes for resistance
OR RECOGNITION OF, HOST
o Arildone – one of the antiviral drugs Horizontal gene transfer – the resistance can
that make us of mode of action. pass/transfer to non-resistant group; side by side
o Pleconaril 3 types of HGT
 Prevents the binding of viruses (poliovirus and
cold virus) to their receptor 1. Transformation – absorb the resistant gene
 Use of peptide and sugar analogs to block through their cell membrane.
attachment of viruses 2. Transduction – need go use vector
- They can copy the structure of receptor. (bacteriophage)
Nililinlang nila ang microbes. 3. Conjugation – requires the use of sex pilus/pili
**In order for the pathogen to infect the host, it needs
Vertical gene transfer – if the microbe undergo
to bind to the host cell first using a LIGAND and a
binary fission (the child could get the copy of the
RECEPTOR. Itong microbial agent ang tina target nila ay
resistant)
ang receptor. Para hindi na ma recognize ng receptor
ang peptidoglycan na nasapathogen. Pag nag fail ma Mechanisms of Resistance
attach ng pathogen sa host cell niya, hindi magiging
*Efflux pump
successful in invading and infecting the host cell.
*Alternative pathway
 *Inactivating enzyme

*Impermeable cell membrane

*Change in cell structure

**side effect of antimicrobial drug is you will

become allergic to antibiotic. Skin test first –
intradermal (administered through IV , antibiotic),

2. People may become allergic to antibiotic.

- May result to hives or anaphylactic shock
(pagputok ng blood vessels and constrict the air
passage, or trachea and it is fetal)
3. Many chemotherapeutic drugs are toxic to
humans.
- Chloramphenicol – aplastic anemia
- Streptomycin – deafness (auditory nerve
damage)
- Metronidazole (antiprotozoal drug)– “black
hairy tongue”(just pigment that goes in the
taste bud)
4. With prolonged use, the broad-spectrum
antibiotics may destroy the normal microflora
and thus becomes much more susceptible to
infectious caused by opportunists or secondary
invaders.
*Microflora – share similarities with pathogenic
microbes.

Considerations:

1. Should be under physician’s supervision.

2. Proper dosage administered for the
recommended period.
3. Immunization
- Pneumonia, flu, meningococcal, swine flu, HPV

*the bigger the zone of inhibition, it is more effective.

Kirby-Bauer Disk Diffusion Assay

MIC – minimum inhibitor concentration

Ex: antibiotic gentamycin (30 micrograms per liter)