AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo.

Ky V Hoang,James R Fitch,John S Gunn,Haley E Adcox,Larry S Schlesinger,Heather M Curry,Peter White,David M Gordon

doi:10.3389/fmicb.2017.01695

Abstract

Francisella tularensis (F. tularensis) is the causative agent of tularemia and is classified as a Tier 1 select agent. No licensed vaccine is currently available in the United States and treatment of tularemia is confined to few antibiotics. In this study, we demonstrate that AR-13, a derivative of the cyclooxygenase-2 inhibitor celecoxib, exhibits direct in vitro bactericidal killing activity against Francisella including a type A strain of F. tularensis (SchuS4) and the live vaccine strain (LVS), as well as toward the intracellular proliferation of LVS in macrophages, without causing significant host cell toxicity. Identification of an AR-13-resistant isolate indicates that this compound has an intracellular target(s) and that eﬄux pumps can mediate AR-13 resistance. In the mouse model of tularemia, AR-13 treatment protected 50% of the mice from lethal LVS infection and prolonged survival time from a lethal dose of F. tularensis SchuS4. Combination of AR-13 with a sub-optimal dose of gentamicin protected 60% of F. tularensis SchuS4-infected mice from death. Taken together, these data support the translational potential of AR-13 as a lead compound for the further development of new anti-Francisella agents.

Highlights

Francisella tularensis subspecies tularensis (F. tularensis) is a remarkably infectious facultative intracellular bacterium and the etiologic agent of tularemia, a zoonotic disease
In this study we report that AR-13, an AR-12 derivative with known antimicrobial activity against multi-drug resistant Mycobacterium tuberculosis and Staphylococcal spp. [compound 33 in (19)], has direct antimicrobial activities against Francisella species with distinct modes of action compared with AR-16
We found that two compounds, AR-16 and AR-13, have the ability to inhibit the growth of several Francisella subspecies with minimum inhibitory concentrations (MICs) at 24 h post-inoculation of 2.5 μg/ml for F. tularensis live vaccine strain (LVS) (Figure 2A) and F. tularensis SchuS4, and 5 μg/ml for F. novicida

Summary

Introduction

Francisella tularensis subspecies tularensis (F. tularensis) is a remarkably infectious facultative intracellular bacterium and the etiologic agent of tularemia, a zoonotic disease. Holarctica (Type B) is somewhat less virulent and other Francisella subspecies/species are considered non-pathogenic to humans (Staples et al, 2006; Oyston, 2008). F. tularensis can be spread via aerosol transmission, resulting in significant morbidity and mortality on a target population (Gurcan, 2014). These traits place this bacterium as a potential biological warfare agent: a Tier 1 Biological Select Agents or Toxins as determined by the United States Department of Health and Human Services (Oyston et al, 2004; Oyston, 2008)

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