host directed therapies to treat infections

why target the host?

gram- are becoming a bigger problem in the clinic - almost all conserved metabolic pathways targeted by current abx, totally drug resistant pathogens are starting to appear

how can targeting the host help?

if deleteious effect of the pathogen can be prevented, success could be reached!

3 challeges developing drugs that target the host

safety, efficacy, competeing drugs

ED50 descr

dose required to produce a therapeutic effect in 50% of the population

TD50 descr

dose required to produce a toxic effect in 50% of the population

what therapeutic index is preferable

high! important to understand the therepeutic index (TI) of a compound as soon as possible, so can stop development on those w/ poor TI

when is targeting the host instead of the pathogen a viable option (3)

preventing entry (in clinic for viruses), MDR pathogens (not in clinic yet - additional benefit that resistance not expected), prevent vectors from transmitting pathogens (not in practice yet)

eg of host modulator in practice

viral entry inhibitors for HIV - maraviroc (against CCR5) and plerixavor (against CXCR4)

pros/cons of entry blockers

pro - limit CD4 T cell infection by HIV
con - not a cure

2 types of HIV infections

successful and abortive - 95% is abortive, no viral replication but still cell death

what benefit does targetting caspase 1 bring?

prevents lymphoid CD4 T cell death by HIV-1, esp if w/ an orally bioavailable and safe drug

caspase I inhibitors pros/cons

pros - limites CD4 T cell killing by HIV
cons - suppression of the immune system, not a cure

possible way to cure HIV

gene editing - excision of HIV-1 DNA by gene editing

pros/cons of gene editing for HIV

pro - eliminates the virus
con - off target gene editing could cause cancer, not done systematically in humans yet, resistance by mutation can occur

way to affect host w/ mycobacterial infections

limitation of nutrients and/or dissemination by preventing vascularization

vascularization inhibitors pros/cons

pros - limit mycobacterial dissemination, approved drugs available, spares the commensal micro flora
cons - disruptive to microvasculature in several organs

how does VEGF work

it induces sprouting of blood vessels - so inhibitors prevent dissemination

novel treatment for malaria

prevent malaria by preventing the vector from transmitting the pathogen - using gene drive (which makes it so that nearly 100% of offspring inherit the modified gene) and exogenous insertion

what can we do for s aureus infections

eradication of intracellular bacteria w/ the help of host enzymes

ADC long

antibody drug conjugates

AAC long

antibody antibiotic conjugates

AAC mode of action

A aureus opsonization, Fc mediated uptake of bacteria, release of antibiotic inside phagolysosome, intracellular killing of bacteria

AAC pros/cons

pros - high [] of abx at the infectious site, long half life of AAC in circulation, use of otherwise toxic abx, spares the commensal micro flora
cons - applicable for a limited number of pathogens (intracellular), expensive, intravenous delivery