Challenges of Drug Resistance and Discovery

What are three mechanisms of drug resistance?

prevent entry or expel of antibiotics

prevent antibiotics from binding the target

reverse binding of antibiotics of targets

why are antibiotics considered secondary metabolites?

they often have no apparent primary use in the producing organism

how does antibiotic resistance develop?

through gene duplication and/or mutations

also through horizontal gene transfer

horizontal gene transfer

conjugation, transduction, and transformation

preventing entry or expel of antibiotics

destroy the antibiotic before it enters the cell

decrease membrane permeability across the outer membrane

how do cells destroy the antibiotic before it enters the cell?

the beta-lactamase enzyme specifically destroys teh beta-lactam antibiotics

how do cells decrease membrane permeability across the outer membrane?

Gram - bacteria generally have an inherent resistance to some antibiotics due to the presence of an outer membrane

Multidrug resistance (MDR) Efflux pumps

dangerous because they can expel many kinds of antibiotics with little regard to structure

what kinds of antibiotics do MDR efflux pumps expel?

beta-lactams

tetracyclines

fluoroquinolones

how do cells prevent antibiotics from binding to the target?

modify the target so that it no longer binds to the antibiotic

add modifying groups that inactivate the antibiotic

how do cells modify the target so that it no longer binds the antibiotic

mutations in key penicillin binding proteins and ribosomal proteins confer resistance to methicillin and streptomycin, respectively

cells that add modifying groups that inactivate the antibiotic

three classes of enzymes are used to modify and inactivate the aminoglycoside antibotics

aminoglycoside inactivating enzymes

• aminoglycoside contain a cyclohexane ring and amino sugars

• aminoglycosides bind 16S rRNA of the 30S subunit and cause translational misreading of the mRNA

• modification of the cyclohexane and/or amino sugars prevents aminoglycosides from binding to the ribosomes

reverse binding of antibiotics to targets

ribosome protection (or rescue)

• Gram-positive organisms can produce proteins that bind to ribosomes and dislodge macrolide (erthormycin) antibiotics bound near the peptidyltrasnferase site

causes of antibiotic resistance

over prescribing antibiotics

patients not finishing their treatment

over-use of antibiotics in livestock and fish farming

lack of hygiene and poor sanitation

lack of new antibiotics being developed

how much has the propotion of antibiotic resistant infections doubled since 2002?

from 5.2% to 11%

what can the presence of drugs do if it doesnt cause antibiotic resistance?

it will kill off or inhibit the growth of competing bacteria that are sensitive

antibiotics are good for treating infectious diseases, but our microbiomes pay the price

disturbing the microbial balance of power in the gut can contribute to inflammatory bowel disease, vitamin deficiency, obesity, and asthma

ESKAPE pathogens

term coined by the Infectious Diseases Society of America

six highly resistant bacterial species that collectively cause about two-thirds of all U.S. nosocomial infections

how to fight antibiotic resistance

Do NOT:

• use antibiotics to treat viral infections

• use an antibiotic if a patients microbiome includes a strain that is resistant to the drug

• prescribe antibiotics before knowing the cause of infection or disease

• without considering the patient needs to take the antibiotic

de-escalate antibiotic usage whenever possible

directly countering drug resistance

-dummy target compounds inactivate resistance enzymes

- alter antibiotics structures so that it sterically hinders access of bacterial modifying enzymes

• Amoxicillin

• Clavulanic acid

finding new antibiotics

• brute force screening microbes, plants, and animals

• combinatorial chemistry

• genome sequence analysis to identify potential bacterial molecular targets

• photosensitive chemicals

interfering with quorom-sensing mechanism (a way microorganisms communicate with each other)

CRISPR-based strategies for reversing antibiotic resistance

antipersister and antibiofilm approaches to antibiotic resistance

• kill persisters directly

• prevent persister formation

• interfere with biofilm formation

• induce biofilm dispersal