Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis

Abstract

cWith phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA-approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT). The treatment of tuberculosis (TB) still takes at least 6 months of multidrug therapy, and adjunctive host-directed therapies (HDTs) have the potential to shorten its duration and prevent drug resistance (1). We have previously shown that type 3 and 5 phosphodiesterase inhibitors (PDE-Is) (cilostazol and sildenafil, respectively) are beneficial in shortening TB first-line standard treatment (2). While type 4 PDE-I (PDE4-I) therapies have been hampered by adverse-effect profiles, two have been approved by the Food and Drug Administration (FDA) since 2011 and others are in development (3). PDE4-Is have recently been studied as adjunctive therapies for TB (1,4). Although the synergism of the PDE4-I CC-3052 with isoniazid (INH) has been reported (5), our group found that, when used as part of a complete tuberculosis multidrug regimen, the PDE4-I rolipram was detrimental to bacterial clearance (6). Since PDE4 has four subtypes (PDE4A to -D), with at least 25 splice variants (7), these contradictory observations may be due to action on different PDE isoforms and the different isoform tissue distributions (7). Additionally, off-target effects or effects on the pharmacokinetics of anti-TB drugs cannot be ruled out.At the start of this study, the only PDE4-I approved by the FDA was roflumilast (trade names, Daxas and Daliresp) (8). Roflumilast is indicated for the management of severe chronic obstructive pulmonary disease (COPD). This agent induces accumulation of host cyclic AMP (cAMP) in lung cells, blocks neutrophil recruitment, and reduces inflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), all of which delay the progression of lung pathology in COPD. To determine whether these anti-inflammatory, tissue-protective effects of roflumilast might also be useful in the management of TB, we assessed the effect of roflumilast as an adjunctive, host-directed therapy on (i) the survival of Mycobacterium tuberculosis-infected mice, (ii) lung cytokine levels during infection, and (iii) bacillary burden during monotherapy and combination therapy with isoniazid.Six-week-old female BALB/c mice were aerosol infected with a high dose of M. tuberculosis H37Rv (4.06 Ϯ 0.20 log 10 CFU). Daily oral gavage (5 days per week) of each group of 20 mice was started the day following infection with roflumilast at the anti-inflammatory dose of 5 mg/kg of body weight/day (9) or isoniazid at 25 mg/kg/day (10) or sham treatment (water). As expected, isoniazid significantly prolonged mouse survival time (P Ͻ 0....

Therapeutic host-directed strategies to improve outcome in tuberculosis

“…Supporting evidence illustrated reduced TNF-α production, thwarted neutrophil recruitment and reduced lung bacillary burden. 35 Similar findings were reported for another selective PDE-4-i, CC-11050, in a TB rabbit model. 36 Analogues of thalidomide, such as CC-3052, have also shown to possess similar PDE-4-i properties and demonstrated potential as TB HDT by reducing lung pathology and inflammation.…”

Myeloid-Derived Suppressor Cells as Target of Phosphodiesterase-5 Inhibitors in Host-Directed Therapeutics for Tuberculosis

“…In various models of TB disease, PDE-I has shown success as an adjunctive treatment agent (17,18). In an 8-week mouse model, roflumilast, an FDA-approved PDE-4i, augmented isoniazid action (19). Further investigation into the exact mechanism of PDE-i success in TB mouse models remains to be determined.…”

“…A case report described a patient with multiple myeloma who, after being treated with a PDE-5 inhibitor, experienced a durable anti-tumor immune response and clinical improvement from reduced MDSC function (72). In the context of pulmonary TB, PDEi has shown to decrease TB disease severity, pathology, and bacillary load in mouse models, but their effect on host immunity during human M.tb infection and TB disease remains poorly defined (17)(18)(19)73).…”

Phosphodiesterase inhibitors as adjunctive therapies for tuberculosis

“…PDE inhibitors are isoenzyme-specific compounds of different binding affinities and potencies that also act according to the tissue distribution of the isozyme ( Wang and Cui, 2006 ). Several PDE inhibitors have already shown varying degrees of success as adjunctive TB treatment agents ( Maiga et al, 2013 , Maiga et al, 2015 ; Subbian et al, 2011 ). Addition of an experimental PDE4 inhibitor—rolipram—to standard TB therapy in the mouse model, for example, had no impact on the rate of bacterial clearance at six months ( Maiga et al, 2013 ).…”

“…Addition of an experimental PDE4 inhibitor—rolipram—to standard TB therapy in the mouse model, for example, had no impact on the rate of bacterial clearance at six months ( Maiga et al, 2013 ). However, more recently roflumilast, an FDA approved PDE4 inhibitor was shown to augment the action of isoniazid in an 8-week mouse model ( Maiga et al, 2015 ). Furthermore, other PDE classes have also shown benefit.…”