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New Drugs and Novel Strategies against Nontuberculous Mycobacteria

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 25701

Special Issue Editors

Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia
Interests: synthesis of new compounds against Mycobacterium tuberculosis and Mycobacterium abscessus
Special Issues, Collections and Topics in MDPI journals
Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy
Interests: mycobacteria; tuberculosis; infection diseases; early drug discovery; nontuberculous mycobacteria; Mycobacterium tuberculosis; Mycobacterium abscessus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nontuberculous mycobacteria (NTM) are opportunistic pathogens, causing pulmonary diseases largely in immunocompromised patients or patients with pre-existing lung conditions, such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis (CF). The NTM incidence (3.3 to 22.6%) is growing in particular among CF patients worldwide. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) are the most commonly identified NTM species in CF individuals. Among NTM species, Mycobacterium abscessus is becoming the most rapidly emerging pathogen in CF centers around the world.

NTM lung disease treatment is challenging due to the long and often unsuccessful therapy. In FC patients, MABSC infection accelerates lung function decline more than other bacteria, including Pseudomonas aeruginosa and Burkholderia cepacia. CF patients with MABSC are more likely to require transplant or to die despite drug treatment. M. abscessus eradication is further complicated by the spread of drug-resistant strains. Consequently, the discovery of new drugs is vital for CF patients’ life. Increasing research and drug discovery efforts are mandatory to have significant therapeutic advances for NTM diseases.

With this issue, we would like to invite possible contributors that study new drugs and novel strategies against these emerging pathogens to write a research article or review.

Prof. Maria Rosalia Pasca
Dr. Vadim Makarov
Dr. Giulia Degiacomi
Guest Editors

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Keywords

  • nontuberculous Mycobacteria
  • Mycobacterium abscessus
  • lung diseases
  • cystic fibrosis
  • new drugs
  • cellular targets
  • drug resistance
  • mechanism of action of new drugs
  • emerging bacterial pathogens
  • therapy

Related Special Issue

Published Papers (7 papers)

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Research

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16 pages, 2715 KiB  
Article
The Antimalarial Mefloquine Shows Activity against Mycobacterium abscessus, Inhibiting Mycolic Acid Metabolism
Int. J. Mol. Sci. 2021, 22(16), 8533; https://doi.org/10.3390/ijms22168533 - 08 Aug 2021
Cited by 4 | Viewed by 2482
Abstract
Some nontuberculous mycobacteria (NTM) are considered opportunistic pathogens. Nevertheless, NTM infections are increasing worldwide, becoming a major public health threat. Furthermore, there is no current specific drugs to treat these infections, and the recommended regimens generally lack efficacy, emphasizing the need for novel [...] Read more.
Some nontuberculous mycobacteria (NTM) are considered opportunistic pathogens. Nevertheless, NTM infections are increasing worldwide, becoming a major public health threat. Furthermore, there is no current specific drugs to treat these infections, and the recommended regimens generally lack efficacy, emphasizing the need for novel antibacterial compounds. In this paper, we focused on the essential mycolic acids transporter MmpL3, which is a well-characterized target of several antimycobacterial agents, to identify new compounds active against Mycobacterium abscessus (Mab). From the crystal structure of MmpL3 in complex with known inhibitors, through an in silico approach, we developed a pharmacophore that was used as a three-dimensional filter to identify new putative MmpL3 ligands within databases of known drugs. Among the prioritized compounds, mefloquine showed appreciable activity against Mab (MIC = 16 μg/mL). The compound was confirmed to interfere with mycolic acids biosynthesis, and proved to also be active against other NTMs, including drug-resistant clinical isolates. Importantly, mefloquine is a well-known antimalarial agent, opening the possibility of repurposing an already approved drug, which is a useful strategy to reduce the time and cost of disclosing novel drug candidates. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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14 pages, 2912 KiB  
Article
Etamycin as a Novel Mycobacterium abscessus Inhibitor
Int. J. Mol. Sci. 2020, 21(18), 6908; https://doi.org/10.3390/ijms21186908 - 21 Sep 2020
Cited by 9 | Viewed by 2867
Abstract
The increase in drug-resistant Mycobacterium abscessus, which has become resistant to existing standard-of-care agents, is a major concern, and new antibacterial agents are strongly needed. In this study, we introduced etamycin that showed an excellent activity against M. abscessus. We found [...] Read more.
The increase in drug-resistant Mycobacterium abscessus, which has become resistant to existing standard-of-care agents, is a major concern, and new antibacterial agents are strongly needed. In this study, we introduced etamycin that showed an excellent activity against M. abscessus. We found that etamycin significantly inhibited the growth of M. abscessus wild-type strain, three subspecies, and clinical isolates in vitro and inhibited the growth of M. abscessus that resides in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of etamycin in the zebrafish (Danio rerio) infection model was greater than that of clarithromycin, which is recommended as the core agent for treating M. abscessus infections. Thus, we concluded that etamycin is a potential anti-M. abscessus candidate for further development as a clinical drug candidate. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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12 pages, 3778 KiB  
Article
A New Model of Chronic Mycobacterium abscessus Lung Infection in Immunocompetent Mice
Int. J. Mol. Sci. 2020, 21(18), 6590; https://doi.org/10.3390/ijms21186590 - 09 Sep 2020
Cited by 12 | Viewed by 2745
Abstract
Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades, affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited [...] Read more.
Pulmonary infections caused by Mycobacterium abscessus (MA) have increased over recent decades, affecting individuals with underlying pathologies such as chronic obstructive pulmonary disease, bronchiectasis and, especially, cystic fibrosis. The lack of a representative and standardized model of chronic infection in mice has limited steps forward in the field of MA pulmonary infection. To overcome this challenge, we refined the method of agar beads to establish MA chronic infection in immunocompetent mice. We evaluated bacterial count, lung pathology and markers of inflammation and we performed longitudinal studies with magnetic resonance imaging (MRI) up to three months after MA infection. In this model, MA was able to establish a persistent lung infection for up to two months and with minimal systemic spread. Lung histopathological analysis revealed granulomatous inflammation around bronchi characterized by the presence of lymphocytes, aggregates of vacuolated histiocytes and a few neutrophils, mimicking the damage observed in humans. Furthermore, MA lung lesions were successfully monitored for the first time by MRI. The availability of this murine model and the introduction of the successfully longitudinal monitoring of the murine lung lesions with MRI pave the way for further investigations on the impact of MA pathogenesis and the efficacy of novel treatments. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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Review

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12 pages, 245 KiB  
Review
Alternative and Experimental Therapies of Mycobacterium abscessus Infections
Int. J. Mol. Sci. 2020, 21(18), 6793; https://doi.org/10.3390/ijms21186793 - 16 Sep 2020
Cited by 25 | Viewed by 4505
Abstract
Mycobacterium abscessus is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, [...] Read more.
Mycobacterium abscessus is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations, e.g. vancomycin–clarithromycin and dual beta-lactam therapy, have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as in intracellular and/or animal models, most have little if any evidence of effect in human infections. Clinical studies of M. abscesssus treatments are needed to reliably determine the value of their incorporation in therapeutic regimens. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
25 pages, 11073 KiB  
Review
MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections
Int. J. Mol. Sci. 2020, 21(17), 6202; https://doi.org/10.3390/ijms21176202 - 27 Aug 2020
Cited by 19 | Viewed by 4603
Abstract
Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The [...] Read more.
Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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12 pages, 1201 KiB  
Review
Divergent Effect of Cigarette Smoke on Innate Immunity in Inflammatory Bowel Disease: A Nicotine-Infection Interaction
Int. J. Mol. Sci. 2020, 21(16), 5801; https://doi.org/10.3390/ijms21165801 - 13 Aug 2020
Cited by 13 | Viewed by 4824
Abstract
Cigarette smoke (CS) has adverse effects in patients with Crohn’s disease (CD), an inflammatory bowel disease (IBD) that has been associated with microbial infection, immuno-dysregulation, and mucosal dysfunction. However, CS seems to provide relief and protection to patients with another IBD known as [...] Read more.
Cigarette smoke (CS) has adverse effects in patients with Crohn’s disease (CD), an inflammatory bowel disease (IBD) that has been associated with microbial infection, immuno-dysregulation, and mucosal dysfunction. However, CS seems to provide relief and protection to patients with another IBD known as ulcerative colitis (UC). These two subsets are featured as M1- and M2-mediated responses, respectively. Nicotine is the most active, addictive, and studied ingredient in CS. The mechanism of how nicotine and/or other CS ingredients induce pro-inflammatory or anti-inflammatory phenotypes in IBD patients remains under investigation. Our most recent in vitro nicotine study provided significant insights toward understanding the contradictory effects of nicotine on IBD patients, and it elucidated the mechanistic role of α7nAChR in modulation of macrophages in tobacco smokers. Shifting the beneficial effect of nicotine to a harmful outcome in CD patients was linked to a nicotine-microbe interaction that supports a microbial etiology in CD pathogenesis. Among the most debated pathogens in CD etiology is Mycobacterium avium subspecies paratuberculosis (MAP). Other studies associated nicotine with upregulation of miR-124 expression in macrophages, which led to anti-inflammatory response. This review discusses published work on the role of nicotine in modulation of the innate immune response and subsequent signaling in macrophages in IBD subsets. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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13 pages, 299 KiB  
Review
Efflux Pump Inhibitors against Nontuberculous Mycobacteria
Int. J. Mol. Sci. 2020, 21(12), 4191; https://doi.org/10.3390/ijms21124191 - 12 Jun 2020
Cited by 21 | Viewed by 3026
Abstract
Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the [...] Read more.
Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described. Full article
(This article belongs to the Special Issue New Drugs and Novel Strategies against Nontuberculous Mycobacteria)
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