Correlative Light Electron Ion Microscopy reveal<i>in vivo</i>localisation of bedaquiline in<i>Mycobacterium tuberculosis</i>infected lungs

Fearns, Antony; Greenwood, Daniel J.H.; Rodgers, Angela; Jiang, Haibo; Gutierrez, Maximiliano G.

doi:10.1101/2020.08.05.237537

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…For example, if IL-6 imparts an inhibitory role in the current model, targeting IL-6 may increase bactericidal activity further. Moreover, due to the ability of bedaquiline to compartmentalise within subcellular regions of macrophages, DFX may also traffic to the same subcellular locations contributing to this synergistic effect [ 42 , 43 ]. As one of the mechanisms of resistance to bedaquiline are mutations leading to the overexpression of the MmpS5-MmpL5 efflux system, a pump naturally involved in siderophore transport, this could indicate that bedaquiline is not only subject to MmpS5-MmpL5 efflux, but it could also interfere with iron metabolism [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

Cahill

O’Connell

Gogan

et al. 2021

IJMS

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For over 50 years, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, we assessed whether manipulating iron levels in macrophages infected with mycobacteria offered some insight into improving current antimicrobials that are used to treat drug-resistant tuberculosis. We investigated if the iron chelator, desferrioxamine, can support the function of human macrophages treated with an array of second-line antimicrobials, including moxifloxacin, bedaquiline, amikacin, clofazimine, linezolid and cycloserine. Primary human monocyte-derived macrophages were infected with Bacillus Calmette-Guérin (BCG), which is pyrazinamide-resistant, and concomitantly treated for 5 days with desferrioxamine in combination with each one of the second-line tuberculosis antimicrobials. Our data indicate that desferrioxamine used as an adjunctive treatment to bedaquiline significantly reduced the bacterial load in human macrophages infected with BCG. Our findings also reveal a link between enhanced bactericidal activity and increases in specific cytokines, as the addition of desferrioxamine increased levels of IFN-γ, IL-6, and IL-1β in BCG-infected human monocyte-derived macrophages (hMDMs) treated with bedaquiline. These results provide insight, and an in vitro proof-of-concept, that iron chelators may prove an effective adjunctive therapy in combination with current tuberculosis antimicrobials.

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Section: Discussionmentioning

confidence: 99%

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

Cahill

O’Connell

Gogan

et al. 2021

IJMS

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“…The relatively long equilibration half-life ( Table 4 ) into lesions and, particularly, caseum, compared to other TB drugs ( 32 ), is consistent with slow creep into caseum. In addition, the high accumulation of SQ109 in immune cells and particularly in foamy macrophages surrounding the necrotic core may act as a reservoir leading to slow drug release, as shown for bedaquiline ( 51 , 52 ), a drug suspected to reach steady state in tissues after several months of daily dosing ( 53 , 54 ). SQ109, like bedaquiline, is a cationic amphiphilic drug (high cLog P [calculated octanol:water partition coefficient] of 7.25 and 6.82 and basic pK a of 8.9 and 6.7 for bedaquiline and SQ109, respectively) involved in phospholipidosis, which has been linked to the differentiation of alveolar macrophages into foamy macrophages upon scavenging of lamellar bodies ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

Egbelowo

Sarathy

Gausi

et al. 2021

Antimicrob Agents Chemother

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SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

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The kinetics of bedaquiline diffusion in tuberculous cavities opens a window for emergence of resistance

Bustion,

Ernest,

Kaya

et al. 2024

Preprint

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Cavitary tuberculosis (TB) is difficult to cure and a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug resistant TB, but emergence of resistance threatens its sustained success. To investigate the role of drug distribution in resistance development, we designed a novel laser-capture microdissection scheme to spatially resolve the penetration of bedaquiline in the necrotic center (caseum) of cavities, a recalcitrant site of disease. Working with preclinical models that form large necrotic lesions, we profiled bedaquiline and two next generation diarylquinolines TBAJ-587 and TBAJ-876. Drug concentrations were measured in laser-captured areas of cavity caseum as a function of time and distance from blood supply. To simulate drug coverage in patient cavities, the data were modeled, and drug penetration parameter estimates were linked to clinical plasma pharmacokinetics for bedaquiline and the new diarylquinolines. Pharmacokinetic-pharmacodynamic (PK-PD) simulations revealed that bedaquiline reaches efficacious concentrations in outer and deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ-587 and TBAJ-876, currently in clinical development, achieve bactericidal concentrations in caseum more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline. Simulations of clinically plausible dosing schemes were conducted to guide the design of clinical trials for cavitary TB and help mitigate resistance development. In summary, the slow kinetics of diffusion of bedaquiline into and out of cavity caseum creates spatio-temporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ-587 and TBAJ-876 predict reduced opportunities for resistance development.

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Correlative Light Electron Ion Microscopy revealin vivolocalisation of bedaquiline inMycobacterium tuberculosisinfected lungs

Cited by 3 publications

References 24 publications

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG

Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

The kinetics of bedaquiline diffusion in tuberculous cavities opens a window for emergence of resistance

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