Managing antibiotic resistance in nontuberculous mycobacterial pulmonary disease: challenges and new approaches

Kwon, Yong Soo; Daley, Charles L.; Koh, Won‐Jung

doi:10.1080/17476348.2019.1638765

Cited by 19 publications

(12 citation statements)

References 117 publications

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“…M. abscessus causes opportunistic pulmonary infections in high-risk patients, including those with cystic fibrosis and bronchiectasis 1,29,31,32 , and can cause pulmonary, skin, and soft tissue infections even in immunocompetent subjects 1,29,31,32 . Importantly, it is emerging as a clinically important strain with an increasing prevalence of antibiotic resistance 33 , although the response rates to antibiotic therapy are somewhat different among subspecies 34 . A mechanistic understanding of the immune profile of NTM disease is needed to develop host-directed therapeutics; however, the key immune biomarkers for patients with Mabc and Mmass infection remain illdefined.…”

Section: Discussionmentioning

confidence: 99%

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

Kim

Lee

et al. 2021

Exp Mol Med

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Infection with rapidly growing nontuberculous mycobacteria is emerging as a global health issue; however, key host factors remain elusive. Here, we investigated the characteristic immune profiles of peripheral blood mononuclear cells (PBMCs) from patients infected with Mycobacteroides abscessus subsp. abscessus (Mabc) and M. abscessus subsp. massiliense (Mmass). Using an integrated analysis of global mRNA and microRNA expression profiles, we found that several inflammatory cytokines/chemokines [interleukin (IL)-1β, IL-6, C-X-C motif chemokine ligand 2, and C-C motif chemokine ligand 2] and miR-144-3p were significantly upregulated in PBMCs from patients compared with those from healthy controls (HCs). Notably, there was a strong correlation between the expression levels of miR-144-3p and proinflammatory cytokines/chemokines. Similarly, upregulated expression of miR-144-3p and proinflammatory cytokines/chemokines was found in macrophages and lungs from mice after infection with Mabc and Mmass. We showed that the expression of negative regulators of inflammation (SARM1 and TNIP3) was significantly downregulated in PBMCs from the patients, although they were not putative targets of miR-144-3p. Furthermore, overexpression of miR-144-3p led to a marked increase in proinflammatory cytokines/chemokines and promoted bacterial growth in macrophages. Together, our results highlight the importance of miR-144-3p linking to pathological inflammation during M. abscessus infection.

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Section: Discussionmentioning

confidence: 99%

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

Kim

Lee

et al. 2021

Exp Mol Med

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“…While the incidence of tuberculosis has declined, infections by nontuberculous mycobacteria (NTM) are increasing ( 1 – 3 ). NTM lung disease is the most common clinical presentation and is primarily caused by members of the Mycobacterium abscessus and Mycobacterium avium complexes ( 4 ). Although they are close relatives of Mycobacterium tuberculosis , these NTM species exhibit differential pathogenesis due to expression of novel surface lipids, adaptation to both host and environmental niches, and acquisition of novel virulence factors ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Piperidine-4-Carboxamides Target DNA Gyrase in Mycobacterium abscessus

Negatu

Beuchel

Madani

et al. 2021

Antimicrob Agents Chemother

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New, more effective drugs for the treatment of lung disease caused by non-tuberculous mycobacteria (NTM) are needed. Among NTM opportunistic pathogens, Mycobacterium abscessus is the most difficult to cure and intrinsically multidrug resistant. In a whole-cell screen of a compound collection active against M. tuberculosis, we previously identified the piperidine-4-carboxamide (P4C) MMV688844 (844) as a hit against M. abscessus. Here, we identified a more potent analog of 844 and showed that both the parent and improved analog retain activity against strains representing all three subspecies of the M. abscessus complex. Furthermore, P4Cs showed bactericidal and anti-biofilm activity. Spontaneous resistance against the P4Cs emerged at a frequency of 10−8/CFU and mapped to gyrA and gyrB encoding the subunits of DNA gyrase. Biochemical studies with recombinant M. abscessus DNA gyrase showed that P4Cs inhibit the wild type enzyme but not the P4C resistant mutant. P4C resistant strains showed limited cross-resistance to the fluoroquinolone moxifloxacin, which is in clinical use for the treatment of macrolide resistant M. abscessus disease, and no cross-resistance to the benzimidazole SPR719, a novel DNA gyrase inhibitor in clinical development for the treatment of mycobacterial diseases. Analyses of P4Cs in recA promotor-based DNA damage reporter strains showed induction of recA promoter activity in wild type but not in P4C resistant mutant background. This indicates that P4Cs, similar to fluoroquinolones, cause DNA gyrase-mediated DNA damage. Together, our results show that P4Cs present a novel class of mycobacterial DNA gyrase inhibitors with attractive antimicrobial activities against the M. abscessus complex.

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“…Resistance to macrolides is of particular concern as this forms the backbone therapy for NTM-PD caused by MAC and M. abscessus , and acts as an alternative therapy to isoniazid in M. kansasii -PD and moxifloxacin in M. xenopi -PD [ 22 ]. In MAC, macrolide resistance can result from modifications of drug binding sites through mutations in the 23S rRNA gene that prevent macrolides binding to ribosomes [ 69 ].…”

Section: Methodsmentioning

confidence: 99%

“…In M. abscessus , macrolide resistance can be intrinsic owing to the presence of the ribosomal methyltransferase gene erm (41). Erm (41) can also be induced to provide resistance to macrolides over time, whereas in M. kansasii , resistance to rifampicin can be acquired via mutations in the gene coding for RNA polymerase [ 69 ].…”

Section: Methodsmentioning

confidence: 99%

Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

Laan¹,

Snabilié²,

Obradović³

2022

Respir Res

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Non-tuberculous mycobacterial pulmonary disease (NTM-PD) poses a substantial patient, healthcare, and economic burden. Managing NTM-PD remains challenging, and factors contributing to this include morphological, species, and patient characteristics as well as the treatment itself. This narrative review focusses on the challenges of NTM-PD from the perspective of the organism and the disease process. Morphological characteristics of non-tuberculous mycobacteria (NTM), antimicrobial resistance mechanisms, and an ability to evade host defences reduce NTM susceptibility to many antibiotics. Resistance to antibiotics, particularly macrolides, is of concern, and is associated with high mortality rates in patients with NTM-PD. New therapies are desperately needed to overcome these hurdles and improve treatment outcomes in NTM-PD. Amikacin liposome inhalation suspension (ALIS) is the first therapy specifically developed to treat refractory NTM-PD caused by Mycobacterium avium complex (MAC) and is approved in the US, EU and Japan. It provides targeted delivery to the lung and effective penetration of macrophages and biofilms and has demonstrated efficacy in treating refractory MAC pulmonary disease (MAC-PD) in the Phase III CONVERT study. Several other therapies are currently being developed including vaccination, bacteriophage therapy, and optimising host defences. Newly developed antibiotics have shown potential activity against NTM-PD and include benzimidazole, delamanid, and pretomanid. Antibiotics commonly used to treat other infections have also been repurposed for NTM-PD, including clofazimine and bedaquiline. Data from larger-scale studies are needed to determine the potential of many of these therapies for treating NTM-PD.

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Managing antibiotic resistance in nontuberculous mycobacterial pulmonary disease: challenges and new approaches

Cited by 19 publications

References 117 publications

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

Piperidine-4-Carboxamides Target DNA Gyrase in Mycobacterium abscessus

Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

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