microfinal: antimicrobial resistance

Paul Ehrlich

-developed concept of selective toxicity

-identified dyes that effectively treated African sleeping sickness

Sahachiro Hato

working with Ehrlich, identified arsenic compounds that effectively treated syphilis

Gerhard Domagk

discovered sulfa drugs

Selman Waksman

discovered streptomycin as a cure for TB

selective toxicity

ability of drug to kill or inhibit pathogen while damaging host as little as possible

therapeutic dose

drug level required for treatment of an infection

toxic dose

drug level at which drug becomes too toxic for patient

therapeutic index

the ratio between the toxic and therapeutic concentrations of a drug

side effects

undesirable effects of drugs on host cells

cidal agents

kill microbes

static agents

inhibit the growth of microorganisms

what are the two types of drug resistance

1. intrinsic: occurs due to a property of the microbe itself

--> mycoplasma resistance to beta-lactam antibiotics and cell wall inhibitors because NO cell wall

2. acquired: occurs when change in genome of a bacterium that converts it from sensitive to resistant

drug tolerant bacteria

lack the mechanisms for antibiotic resistance and "ignore" the presence of antibiotics, usually because they are embedded in biofilms that antibiotics cannot effectively penetrate or are growing too slowly to be inhibited.

antibiotics are secondary metabolites

- they have no apparent primary use in producing organism

- not essential for survival But enhance survival

how many basic antibiotic resistant mechanisms are there

4

1. modify the target of antibiotic so that it can't bind

mutations in ribosomal proteins confer resistance to streptomycin because it changes the shape of 30s subunit

2. destroy antibiotic before it gets into the cell

- drug inactivation

- beta-lactamaze enzyme destroys pcn

3. minimize concentration in cell by modifiying groups that inactivate antibiotic

3 enzyme types

4. pump antibiotics out of cell (eflux pump)

pump wide range of drugs before they can do any damage

antibiotic resistance develops through gene duplications/mutations

- vertical evolution: mutation passed to offspring

- horizontal gene transfer is MORE common

--> C, C, T

how to overcome resistance

- give appropriate concentration

- give 2 or more drugs at once

- use only when needed

--> consider other possible treatments (phages)

drug discovery process

1. identify new targets

2. design compounds to inhibit targets

3. alter compound to optimize MIC

4. determine compounds spectrum

future of drug discovery

1. nanotubes= poke holes in bacterial cell membrane

2. molecules that "cork" type III secretion apparatus

---> makes efflux pumps inactive