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2015 ; 264
(1
): 344-62
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New tricks for old dogs: countering antibiotic resistance in tuberculosis with
host-directed therapeutics
#MMPMID25703571
Hawn TR
; Shah JA
; Kalman D
Immunol Rev
2015[Mar]; 264
(1
): 344-62
PMID25703571
show ga
Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50
years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently
needed for resistant strains, shortening duration of treatment, and targeting
different stages of the disease, especially for treatment during human
immunodeficiency virus co-infection. One solution to the conundrum that
antibiotics kill the bacillus yet select for resistance is to target the host
rather than the pathogen. Here, we discuss recent progress in so-called
'host-directed therapeutics' (HDTs), focusing on two general mechanistic
strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii)
immunomodulatory HDTs that facilitate protective immune responses that kill Mtb
or reduce deleterious responses that exacerbate disease. HDTs hold significant
promise as adjunctive therapies in that they are less likely to engender
resistance, will likely have efficacy against antibiotic-resistant strains, and
may have activity against non-replicating Mtb. However, TB is a complex and
variegated disease, and human populations exhibit significant diversity in their
immune responses to it, which presents a complicated landscape for HDTs to
navigate. Nevertheless, we suggest that a detailed mechanistic understanding of
drug action, together with careful selection of disease stage targets and dosing
strategies may overcome such limitations and allow the development of HDTs as
effective adjunctive treatment options for TB.
|*Drug Resistance, Bacterial
[MESH]
|*Host-Pathogen Interactions
[MESH]
|Animals
[MESH]
|Antitubercular Agents/*pharmacology/*therapeutic use
[MESH]