CH15 - Antimicrobial Drugs

Antimicrobial drugs

Can be classified as antibacterial, antifungal, and antiviral agents.

antibiotic

substance produced by one microbe that can inhibit the growth or viability of another microbe.

antibiotics, synthetic

Antimicrobial drugs consist of ___ and ____ compounds

Penicillin

the first antibiotics widely used in clinic. It is produced by the fungus Penicillium and inhibits the growth of staphylococci

staphylococi

Penicillin is the first antibiotics widely used in clinic.

• It is produced by the fungus Penicillium and inhibits the growth of ____

Arsphenamine, sulfonamides

_____ , and _____ are among the earliest examples of synthetic compounds for the treatment of infectious diseases.

Paul Ehrlich

____ was the discoverer of both arsphenamine and the receptor concept

syphilis

Arsphenamine: the first modern antibacterial drug

• An organic arsenic compound that was dubbed “salvarsan” and clinically used to treat ____ for several decades

Sulfonamides

the first effective drugs for the treatment of systemic bacterial infection

Gerhard Domagk

_____ Discovered Prontosil

viruses, bacteria, fungi, parasites,, protozoa, metazoa

Diversity of infectious pathogens

• Viruses

• Bacteria

• Fungi

• Parasites – eukaryotes other than fungi

  • ____ – unicellular

  • ___ – multicellular

inactive, sulfanilamide, dihydropteroate , folate, stops

How does Prontosil work?

• Prontosil itself is ___ in vitro ( lab setting)

• In the body, it is metabolized into ____ (active form)

• This active form

○ Inhibits ____ synthase

○ Blocks ___synthesis in bacteria

→ prevents DNA synthesis → ___ bacterial growth

gram, prior, immunostaining, PCR, isothermal, unique

Identifying the infecting organism

1. ___ staining: a rapid assessment

2. Cultivation of a sample taken ___ to initiating treatment for conclusive diagnosis & antibiotics susceptibility analysis

3. Detection of unique microbial antigens using immunostaining

4. Detection of unique microbial RNA or DNA using ___ or ___ nucleic acid amplification

5. Detection of the ___ patterns of host immune response

-cidal, -ostatic

Types of antimicrobial agents: ___ vs ____

beta lactams, penicillin, chloramphenicol

Types of antimicrobial agents: -cidal vs -ostatic

• Bactericidal: killing outright (e.g., ___ , ___ )

• Bacteriostatic: stalling proliferation (e.g., ___ )

bactericidal

drugs able to effectively kill more than 99.9% bacteria within 18 to 24 hours of incubation

bacteriostatic

drugs that only arrest the growth and replication of bacteria at drug levels achievable in the patient.

MIC

minimum inhibitory concentration

MIC

lowest antimicrobial concentration that PREVENTS the visible growth of an organism after 24 h of incubation

susceptibility, sensitivity, resistance

Based on MIC, a pathogen can be classified as:

• Having ___ to the agent

• Having intermediate ___ to the agent

• Having ___ to the agent

4,10

The peak serum concentration of a drug should be ___ to __ times greater than the MIC in order for a pathogen to be susceptible

MBC

minimum bactericidal concentration

MBC

the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations.

varying, 24, inhibits

MIC Determination

• Tubes containing ___ concentration of antibiotic are inoculated with test organism

• Growth of microorganism is measured after __ hours of incubation

• MIC is the lowest concentration of antibiotic that ___ bacterial growth

varying, subculture, 24, kills

MBC Determination

• Tubes containing ___ concentration of antibiotic are inoculated with test organism

• After 24 hours of incubation in the presence of antibiotic, ___in antibiotic-free medium, and measure growth after __ hours of incubation

• MBC is the lowest concentration of antibiotic that ___ 99.9% of bacteria (equals 32 in this example)

4,64

Concentration-dependent killing

Certain antimicrobial agents show a significant increase in the rate of bacterial killing as the concentration of antibiotic increase from ___ to ___fold the MIC of the drug for the infecting organism

above

Time-dependent killing

• clinical efficacy of agents can also be predicted by the % of time that blood concentrations of a drug remain ___ the MIC

• Extended (generally 3 to 4 hours) or continuous (24 hours) infusions can be utilized instead of intermittent dosing to achieve prolonged time above the MIC and kill more pathogen

below, 1

Post-antibiotic effect (PAE)

• This is a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC.

• Agents exhibiting a LONG PAE often require only ___ dose per day

narrow, broad, extended

Based on their range of antimicrobial activity, antimicrobial drugs can be characterized as ___ spectrum, ____ spectrum, or ___ spectrum.

Narrow

____ spectrum: active against a single species or a limited group of pathogens (e.g., Gram-positive bacteria).

gram positive

Narrow spectrum: active against a single species or a limited group of pathogens (e.g., _____bacteria).

specific, without

Narrow-spectrum drugs are sometimes preferred because they target a ____ pathogen ___ disturbing the normal flora of the gut or respiratory tract.

Broad

____ spectrum: active against a wide range of pathogens

initial, not

Broad-spectrum drugs are sometimes preferred for the ___ treatment of an infection when the causative pathogen is ___ yet identified

Extended

____ spectrum: intermediate range of activities.

host, resistance

Challenges of antimicrobial drug discovery (2)

• The drugs must kill the microbes but ___ the host (the principle of selective toxicity)

• Microbes tend to develop ___ to drugs that are initially effective

mutation, plasmid, already

Microbes tend to develop ___ to drugs that are initially effective

• From ___ and selection

• From the transfer of ___ that confer drug resistance

• For antibiotics: resistance genes ___ exist in the producers of antibiotics, which can spread to pathogenic bacteria by gene transfer

penicillin, sulfonamides

Drug targets for antimicrobial therapy - Macromolecules that occur in the cells of the pathogen but not within the human host.

• The bacterial cell wall ( ___ )

• de novo synthesis of folic acid ( ___ )

chloramphenicol, trimethoprim, ciprofloxacin

Drug targets for antimicrobial therapy - Macromolecules that occur in both humans and the pathogen but are structurally divergent.

• Ribosomes ( ___ )

• Dihydrofolate reductase ( ___ )

• DNA topoisomerase ( ___ )

Formylmethionine deformylase

Drug targets for antimicrobial therapy -Essential pathogen genes revealed by genome

sequencing and genetic studies

• ____ ____

Dihydrofolate reductase:

an example of a drug target with sufficient structural difference between the host and the pathogen

wall, membrane, DNA/RNA, protein, metabolism

Drug targets for antimicrobial therapy

• Cell ___ synthesis

• Cell ___ function

• ___ synthesis

• ___ synthesis

• Intermediate ___

acetylase, Beta-lactamase

Mechanisms of anti-microbial resistance - Inactivation of the drug by microbial enzymes

• inactivation of aminoglycosides by ____;

• inactivation of Beta-lactam antibiotics by ____

porin, ABC,

Mechanisms of anti-microbial resistance - Decreased accumulation of the drug by the microbe

• via DEC uptake (e.g., ___ mutation)

• via INC efflux ( ___ transporter P-glycoprotein)

sulfonamides, beta lactam

Mechanisms of anti-microbial resistance - Reduced affinity of the target molecule for the drug

• e.g., reduced affinity of folate synthesis enzymes for ___ ;

• e.g., reduced affinity of penicillin-binding proteins for ____ antibiotics

resistance, germs

Antibiotics fight germs (bacteria and fungi). But germs fight back and find new ways to survive.

• Their defense strategies are called resistance mechanisms.

• Only ___, not people, become resistant to antibiotics.

DNA gyrase

Alteration in the target enzyme ____ ____ resulted in resistance to fluoroquinolones

b lactamases

Enterobacter is resistant to cephalosporins by producing _____

antibiotics, transfer

Resistance genes exist in producers of ___

• can spread to pathogenic bacteria by gene ___

bacteria, plasmids, transposons

Drug resistance in bacterial populations can be spread:

• from person to person by ___

• from bacterium to bacterium by ___

• from plasmid to plasmid (or chromosome) by ___.

conjugative

The main method of transfer of resistance genes from one bacterium to another is by ___ plasmids.

• The bacterium forms a connecting tube ( sex pilus) with other bacterium through which the plasmids pass.

transduction

A less common method of transfer is by ___

• The transmission by a bacterial virus (phage) bearing a resistance gene into another bacterium

lipoteichoic, thick, no

Gram Positive Cell Wall

• ____ acids

• ___ peptidoglycan layer

• outer membrane?

LPS, porin, MDR

Gram Negative Cell Wall

• Contains ___, ___, and a ____ system

• outer membrane?

mycolic, porin, yes

Mycobacteria Cell Wall

• contains ___ acid and a ___

• outer membrane?

isoniazid

INH is short for ___

KatG, Mycolic

Isoniazid (INH) Mechanism

• INH is activated by a mycobacterial enzyme called ___

• Once activated, it inhibits enzymes involved in synthesizing ___ acids ( essential components of the waxy cell wall of mycobacteria)

• Weakens the cell wall → bacteria die

PEP, Fosfomycin, alanine racemase, D-alanine ligase, seromycin, removed, glycine, Lipid II, Bacitracin, Transpeptidase,  penicillin G , Vancomycin

bacterial peptidoglycan synthesis pathway

• NAG ( hexomeric glucose) is bound to UDP ; ___ adds a Lactose group to it

  • ____ can inhibit this step ( used to treat UTI infections) This is cuz it’s similar to PEP structure wise

• 3 L-amino and 2 D-ala groups are added to it

  • 2 L-Ala - ( alanine racemase) -> 2 D-La - (D-alanine ligase)-> D-Ala-D-Ala

  • ____ acts as a competitive inhibitor for this rxn

• UDP group is ____ and the remnants bind to Undecaprenol phosphate

• Another NAG-U group is added

• 5 ___ molecules are added

• The structure becomes ____ '

• Lipid II ___ and goes to the outside of the cell

  • ___ can inhibit this step

• Leaves the undecaprenol group, and more sugars are bound together to form the peptidoglycan

• ___ allows the glycine of one molecule to combine with the amino acids of another molecule

  • ___ is a suicide inhibitor of transpeptidase, making it irreversibly inhibited

negative, amide, COOH

Ampicillin and ticarcillin can pass the membrane of gram ___ bacteria

○ Ampicillin has an ___ group

○ Ticarcillin has a ___ group, which both inc the polarity ( hydrophillic) and pass the porin

methicillin

____ has INC resistance to B-lactamase

imipenem

_____ is susceptible to metallo-B-lactamase

clavulanic acid

____ inhibits b-lactamase

Vancomycin

_____ sequesters the substrate of the transpeptidase reaction

positive

Vancomycin is active against Gram ___ bacteria

positive, holes, depolarization

Daptomycin

• cyclic lipopeptide antibiotic for treating infections caused by resistant gram ___ organisms.

• It inserts into the cell membrane, aggregates, and creates ___ that leak ions.

• This causes rapid ___ , resulting in a loss of membrane potential.

Daptomycin

A cyclic lipopeptide antibiotic for treating infections caused by resistant gram-positive organisms.

concentration

Daptomycin is a ( time / concentration) dependent bacteria

Polymyxin B:

an antibiotics that disrupts outer membrane via binding LPS

negative

Polymyxin B can be used in combination with B-lactam antibiotics to effectively kill Gram ___ bacteria