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Mycobacterial Infections and Therapy

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 42376

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Dr. Luisa Jordao

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Instituto Nacional de Saúde Doutor Ricardo Jorge, Departamento de Saúde Ambiental, Unidade de Investigação e Desenvolvimento, Avenida Padre Cruz, 1649-016 Lisboa, Portugal
Interests: biofilms; environmental microorganisms; mycobacteria; infection; microscopy
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Dr. Ines Joao

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Instituto Nacional de Saúde Doutor Ricardo Jorge, Departamento de Saúde Departamento de Doenças Infeciosas, Laboratório Nacional de Referência de Micobactérias. Avenida Padre Cruz, 1649-016 Lisboa, Portugal
Interests: mycobacteria; molecular taxonomy; tuberculosis; molecular diagnosis

Special Issue Information

Dear Colleagues,

Mycobacterial infections are as old as humankind nevertheless remain an important public health issue. Tuberculosis is the best known mycobacterial infection but in the latest decades infections by nontuberculous mycobacteria gained relevance. Among the challenges to fight, mycobacterial infections are the increase of multidrug resistant strains, biofilm related infections, the lack of new effective drugs and therapeutic approaches. In order to solve this problem it is important to increase our knowledge on mycobacteria identification/ characterization, pathogenesis and bring new candidates to drug discovery pipeline.

This issue will explore, but is not restricted to the following topics:

Mycobacteria identification and differentiation to species level
Case reports of infection by non obligatory pathogenic mycobacteria
Mycobacteria pathogenesis (in vitro, ex vivo and in vivo studies) and virulence factors
Drug susceptibility profile and antimicrobial resistance (AMR) mechanisms
Strategies to combat nontuberculous mycobacteria AMR
New/ repurposed conventional and alternative drugs (plants and venoms)
New therapeutic approches (inhaled therapeutics, drug targeting, synergistic drug combination)

Dr. Luisa Jordao
Dr. Ines Joao
Guest Editors

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Keywords

Mycobacteria
Infection
Antimicrobial resistance
Pathogenesis
New drugs
New therapies
Repurposed conventional drugs
Virulence factors
Biofilm
New drugs and therapies

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Published Papers (11 papers)

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Research

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13 pages, 1044 KiB

Open AccessArticle

Exposure of Mycobacterium avium subsp. homonissuis to Metal Concentrations of the Phagosome Environment Enhances the Selection of Persistent Subpopulation to Antibiotic Treatment

by Lia Danelishvili, Elyssa Armstrong, Emily Miyasako, Brendan Jeffrey and Luiz E. Bermudez

Antibiotics 2020, 9(12), 927; https://doi.org/10.3390/antibiotics9120927 - 19 Dec 2020

Cited by 4 | Viewed by 2386

Abstract

Mycobacterium avium subspecies hominissuis (MAH) is an opportunistic intracellular pathogen causing infections in individuals with chronic lung conditions and patients with immune-deficient disorders. The treatment of MAH infections is prolonged and outcomes many times are suboptimal. The reason for the extended treatment is complex and reflects the inability of current antimicrobials to clear diverse phenotypes of MAH quickly, particularly, the subpopulation of susceptible but drug-tolerant bacilli where the persistent fitness to anti-MAH drugs is stimulated and enhanced by the host environmental stresses. In order to enhance the pathogen killing, we need to understand the fundamentals of persistence mechanism and conditions that can initiate the drug-tolerance phenotype in mycobacteria. MAH can influence the intracellular environment through manipulation of the metal concentrations in the phagosome of infected macrophages. While metals play important role and are crucial for many cellular functions, little is known how vacuole elements influence persistence state of MAH during intracellular growth. In this study, we utilized the in vitro model mimicking the metal concentrations and pH of MAH phagosome at 1 h and 24 h post-infection to distinguish if metals encountered in phagosome could act as a trigger factor for persistence phenotype. Antibiotic treatment of metal mix exposed MAH demonstrates that metals of the phagosome environment can enhance the persistence state, and greater number of tolerant bacteria is recovered from the 24 h metal mix when compared to the viable pathogen number in the 1 h metal mix and 7H9 growth control. In addition, bacterial phenotype induced by the 24 h metal mix increases MAH tolerance to macrophage killing in TNF-α and IFN-γ activated cells, confirming presence of persistent MAH in the 24 h metal mix condition. This work shows that the phagosome environment can promote persistence population in MAH, and that the population differs dependent on a concentration of metals. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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11 pages, 3374 KiB

Open AccessArticle

Population Pharmacokinetic Analysis of Amikacin for Optimal Pharmacotherapy in Korean Patients with Nontuberculous Mycobacterial Pulmonary Disease

by Xuanyou Jin, Jaeseong Oh, Joo-Youn Cho, SeungHwan Lee and Su-jin Rhee

Antibiotics 2020, 9(11), 784; https://doi.org/10.3390/antibiotics9110784 - 6 Nov 2020

Cited by 7 | Viewed by 2973

Abstract

Amikacin is used as a therapy for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) who are resistant to macrolide antibiotics or have severe symptoms. This study aimed to characterize the pharmacokinetic properties of amikacin in patients with NTM-PD by developing a population pharmacokinetic model and to explore the optimal pharmacotherapy in patients with NTM-PD. For this study, all data were retrospectively collected. The amikacin pharmacokinetic properties were best described by a two-compartment model with first-order elimination. The estimated glomerular filtration rate and body weight were identified as significant covariates for clearance and the volume of distribution, respectively. A model-based simulation was conducted to explore the probability of reaching the target therapeutic range when various dose regimens were administered according to the body weight and renal function. The simulation results indicated that the amikacin dosage should be determined based on the body weight, and for patients who weigh over 70 kg, it is necessary to adjust the dose according to renal function. In conclusion, the optimal pharmacotherapy of amikacin for patients with NTM-PD was recommended based on the population pharmacokinetic model, which is expected to enable the personalization of drug therapy and improve the clinical outcomes of amikacin therapy. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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13 pages, 4511 KiB

Open AccessArticle

Single Cell Analysis of Drug Susceptibility of Mycobacterium abscessus during Macrophage Infection

by Joanna Brzostek, Amierah Fatin, Wen Hui Chua, Hui Yi Tan, Thomas Dick and Nicholas R. J. Gascoigne

Antibiotics 2020, 9(10), 711; https://doi.org/10.3390/antibiotics9100711 - 17 Oct 2020

Cited by 4 | Viewed by 3564

Abstract

Mycobacterium abscessus is an emerging health risk to immunocompromised individuals and to people with pre-existing pulmonary conditions. As M. abscessus possesses multiple mechanisms of drug resistance, treatments of M. abscessus are of poor efficacy. Therefore, there is an urgent need for new therapeutic strategies targeting M. abscessus. We describe an experimental system for screening of compounds for their antimicrobial activity against intracellular M. abscessus using flow cytometry and imaging flow cytometry. The assay allows simultaneous analysis of multiple parameters, such as proportion of infected host cells, bacterial load per host cell from the infected population, and host cell viability. We verified the suitability of this method using two antibiotics with known activity against M. abscessus: clarithromycin and amikacin. Our analysis revealed a high degree of infection heterogeneity, which correlated with host cell size. A higher proportion of the larger host cells is infected with M. abscessus as compared to smaller host cells, and infected larger cells have higher intracellular bacterial burden than infected smaller cells. Clarithromycin treatment has a more pronounced effect on smaller host cells than on bigger host cells, suggesting that heterogeneity within the host cell population has an effect on antibiotic susceptibility of intracellular bacteria. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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15 pages, 296 KiB

Open AccessArticle

Genetic Identification and Drug-Resistance Characterization of Mycobacterium tuberculosis Using a Portable Sequencing Device. A Pilot Study

by Jorge Cervantes, Noemí Yokobori and Bo-Young Hong

Antibiotics 2020, 9(9), 548; https://doi.org/10.3390/antibiotics9090548 - 27 Aug 2020

Cited by 11 | Viewed by 4296

Abstract

Clinical management of tuberculosis (TB) in endemic areas is often challenged by a lack of resources including laboratories for Mycobacterium tuberculosis (Mtb) culture. Traditional phenotypic drug susceptibility testing for Mtb is costly and time consuming, while PCR-based methods are limited to selected target loci. We herein utilized a portable, USB-powered, long-read sequencing instrument (MinION), to investigate Mtb genomic DNA from clinical isolates to determine the presence of anti-TB drug-resistance conferring mutations. Data analysis platform EPI2ME and antibiotic-resistance analysis using the real time ARMA workflow, identified Mtb species as well as extensive resistance gene profiles. The approach was highly sensitive, being able to detect almost all described drug resistance conferring mutations based on previous whole genome sequencing analysis. Our findings are supportive of the practical use of this system as a suitable method for the detection of antimicrobial resistance genes, and effective in providing Mtb genomic information. Future improvements in the error rate through statistical analysis, drug resistance prediction algorithms and reference databases would make this a platform suited for the clinical setting. The small size, relatively inexpensive cost of the device, as well as its rapid and simple library preparation protocol and analysis, make it an attractive option for settings with limited laboratory infrastructure. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

10 pages, 250 KiB

Open AccessArticle

Active Pulmonary Tuberculosis in Elderly Patients: A 2016–2019 Retrospective Analysis from an Italian Referral Hospital

by Francesco Di Gennaro, Pietro Vittozzi, Gina Gualano, Maria Musso, Silvia Mosti, Paola Mencarini, Carlo Pareo, Antonino Di Caro, Vincenzo Schininà, Enrico Girardi and Fabrizio Palmieri

Antibiotics 2020, 9(8), 489; https://doi.org/10.3390/antibiotics9080489 - 7 Aug 2020

Cited by 46 | Viewed by 4811

Abstract

Tuberculosis (TB) in the elderly (>65 years old) has increasingly become a global health problem. It has long been recognized that older people are vulnerable to developing tuberculosis. We retrospectively evaluated data from patients older than 65 years diagnosed with pulmonary TB admitted to the National Institute for Infectious Diseases L. Spallanzani, Rome, Italy, from 1 January 2016 to 31 December 2019. One hundred and six consecutive patients were diagnosed with pulmonary TB and 68% reported at least one comorbidity and 44% at least one of the TB risk-factors. Out of the 26 elderly patients who reported an adverse event, having risk factors for TB (O.R. (Odds Ratios) = 1.45; 95% CI 1.12–3.65) and the presence of cavities on Chest X-rays (O.R. = 1.42; 95% CI 1.08–2.73) resulted in being more likely to be associated with adverse events in elderly patients. Having weight loss (O.R. = 1.31; 95% CI 1.08–1.55) and dyspnea (O.R. = 1.23; 95% CI 1.13–1.41) resulted in being significant predictors of unsuccessful treatment outcome in elderly patients. Older people with TB represent a vulnerable group, with high mortality rate, with a challenging diagnosis. Hospitalizations in tertiary referral hospital with clinical expertise in TB management can be useful to improve the outcome of these fragile patients. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

16 pages, 2264 KiB

Open AccessArticle

Contact Effect of a Methylobacterium sp. Extract on Biofilm of a Mycobacterium chimaera Strain Isolated from a 3T Heater-Cooler System

by Inés Pradal, Jaime Esteban, Arancha Mediero, Marta García-Coca and John Jairo Aguilera-Correa

Antibiotics 2020, 9(8), 474; https://doi.org/10.3390/antibiotics9080474 - 3 Aug 2020

Cited by 5 | Viewed by 3211

Abstract

Mycobacterium chimaera is an opportunistic slowly growing non-tuberculous mycobacteriumof increasing importance due to the outbreak of cases associated with contaminated 3T heater-cooler device (HCD) extracorporeal membrane oxygenator (ECMO). The aim of this study was to evaluate the effect of pre-treating a surface with a Methylobacterium sp. CECT 7180 extract to inhibit the M. chimaera ECMO biofilm as well as of the treatment after different dehydration times. Surface adherence, biofilm formation and treatment effect were evaluated by estimating colony-forming units (CFU) per square centimeter and characterizing the amount of covered surface area, thickness, cell viability, and presence of intrinsic autofluorescence at different times using confocal laser scanning microscopy and image analysis. We found that exposing a surface to the Methylobacterium sp. CECT 7180 extract inhibited M. chimaera ECMO biofilm development. This effect could be result of the effect of Methylobacterium proteins, such as DNaK, trigger factor, and xanthine oxidase. In conclusion, exposing a surface to the Methylobacteriumsp. extract inhibits M. chimaera ECMO biofilm development. Furthermore, this extract could be used as a pre-treatment prior to disinfection protocols for equipment contaminated with mycobacteria after dehydration for at least 96 h. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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9 pages, 768 KiB

Open AccessArticle

Non-Tuberculous Mycobacteria in Respiratory Specimens of Patients with Obstructive Lung Diseases—Colonization or Disease?

by Monika Szturmowicz, Karina Oniszh, Dorota Wyrostkiewicz, Piotr Radwan-Rohrenschef, Dorota Filipczak and Anna Zabost

Antibiotics 2020, 9(7), 424; https://doi.org/10.3390/antibiotics9070424 - 20 Jul 2020

Cited by 8 | Viewed by 3070

Abstract

Non-tuberculous mycobacteria (NTM) are increasingly a cause of human respiratory tract colonization and mycobacterial lung disease (NTM-LD), especially in patients with chronic lung diseases. The aim of the present study was to find the factors predictive of NTM-LD in patients with obstructive lung diseases and NTM respiratory isolates. A total of 839 isolates of NTM, obtained from 161 patients between 2010 and 2020 in a single pulmonary unit, have been retrospectively reviewed. Of these isolates, 73 concerned 36 patients with obstructive lung diseases (COPD-26, asthma-3, COPD/asthma overlap syndrome-7). NTM-LD was recognized according to the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) criteria in 17 patients, colonization in 19. Lower BMI, elevated body temperature on admission, infiltrative/cavitary lesions on chest CT, and NTM species other than Mycobacterium gordonae were the significant predictors of NTM-LD recognition. Based on the above-mentioned predictive factors, an original scoring system was implemented. The diagnostic utility of the scoring system was higher than that of single parameters. We conclude that NTM-LD prediction in patients with obstructive lung diseases and positive respiratory isolates is difficult. A scoring system based on clinical, radiological and microbiological characteristics was capable of facilitating the differential diagnosis, but it needs further validation in a larger study group. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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Review

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23 pages, 1192 KiB

Open AccessReview

Opportunist Coinfections by Nontuberculous Mycobacteria and Fungi in Immunocompromised Patients

by Ines Joao, Helena Bujdáková and Luisa Jordao

Antibiotics 2020, 9(11), 771; https://doi.org/10.3390/antibiotics9110771 - 2 Nov 2020

Cited by 9 | Viewed by 6034

Abstract

Nontuberculous mycobacteria (NTM) and many fungal species (spp.) are commonly associated with opportunistic infections (OPIs) in immunocompromised individuals. Moreover, occurrence of concomitant infection by NTM (mainly spp. of Mycobacterium avium complex and Mycobacterium abscessus complex) and fungal spp. (mainly, Aspergillus fumigatus, Histoplasma capsulatum and Cryptococcus neoformans) is very challenging and is associated with poor patient prognosis. The most frequent clinical symptoms for coinfection and infection by single agents (fungi or NTM) are similar. For this reason, the accurate identification of the aetiological agent(s) is crucial to select the best treatment approach. Despite the significance of this topic it has not been sufficiently addressed in the literature. This review aims at summarizing case reports and studies on NTM and fungi coinfection during the last 20 years. In addition, it briefly characterizes OPIs and coinfection, describes key features of opportunistic pathogens (e.g., NTM and fungi) and human host predisposing conditions to OPIs onset and outcome. The review could interest a wide spectrum of audiences, including medical doctors and scientists, to improve awareness of these infections, leading to early identification in clinical settings and increasing research in the field. Improved diagnosis and availability of therapeutic options might contribute to improve the prognosis of patients’ survival. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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21 pages, 776 KiB

Open AccessReview

Mycogenic Metal Nanoparticles for the Treatment of Mycobacterioses

by Marta Filipa Simões, Cristiane Angélica Ottoni and André Antunes

Antibiotics 2020, 9(9), 569; https://doi.org/10.3390/antibiotics9090569 - 2 Sep 2020

Cited by 21 | Viewed by 4892

Abstract

Mycobacterial infections are a resurgent and increasingly relevant problem. Within these, tuberculosis (TB) is particularly worrying as it is one of the top ten causes of death in the world and is the infectious disease that causes the highest number of deaths. A further concern is the on-going emergence of antimicrobial resistance, which seriously limits treatment. The COVID-19 pandemic has worsened current circumstances and future infections will be more incident. It is urgent to plan, draw solutions, and act to mitigate these issues, namely by exploring new approaches. The aims of this review are to showcase the extensive research and application of silver nanoparticles (AgNPs) and other metal nanoparticles (MNPs) as antimicrobial agents. We highlight the advantages of mycogenic synthesis, and report on their underexplored potential as agents in the fight against all mycobacterioses (non-tuberculous mycobacterial infections as well as TB). We propose further exploration of this field. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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Other

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6 pages, 1980 KiB

Open AccessCase Report

Mycobacterium szulgai Lung Disease or Breast Cancer Relapse—Case Report

by Anna Kempisty, Ewa Augustynowicz-Kopec, Lucyna Opoka and Monika Szturmowicz

Antibiotics 2020, 9(8), 482; https://doi.org/10.3390/antibiotics9080482 - 5 Aug 2020

Cited by 3 | Viewed by 3319

Abstract

Cancers are one of the risk factors of non-tuberculous mycobacterial (NTM) lung disease. The majority of data in this group of patients concern infections caused by Mycobacterium avium—the most prevalent NTM species worldwide. In contrast, limited information can be found regarding the uncommon NTM such as Mycobacterium szulgai. We present the case of M. szulgai lung disease in a patient with a history of breast cancer. Coexistence of NTM lung disease and breast cancer lung metastasis as well as primary lung cancer was suspected. Finally, neoplastic disease was ruled out based on negative results of endobronchial biopsy and negative tumor markers for lung and breast cancer. M. szulgai lung disease was successfully treated with rifampicin, ethambutol and clarithromycin. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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8 pages, 4608 KiB

Open AccessBrief Report

Structural Modifications of 3-Triazeneindoles and Their Increased Activity Against Mycobacterium tuberculosis

by Konstantin B. Majorov, Boris V. Nikonenko, Pavel Yu. Ivanov, Lyudmila N. Telegina, Alexander S. Apt and Valeria S. Velezheva

Antibiotics 2020, 9(6), 356; https://doi.org/10.3390/antibiotics9060356 - 24 Jun 2020

Cited by 5 | Viewed by 2737

Abstract

We synthesized 100 novel indole-based compounds with polyaza-functionalities, including 3-triazeneindoles, and tested their activity in vitro against laboratory M. tuberculosis H37Rv and clinical izoniazid-resistant CN-40 isolates, using gross and fine titration approaches. Here we present a few 3-triazeneindoles with the highest anti-mycobacterial activity. Introduction of short lipid tails into the 3-triazeneindole core additionally increased their activity against mycobacteria engulfed by murine macrophages. We also demonstrate that the compound TU112, one of the most active in our previous study, being not bioavailable after administration in mice per os, manifests prominent anti-mycobacterial activity after intravenous or aerosol delivery, as assessed by the mouse serum and lung supernatant titration assays. Full article

(This article belongs to the Special Issue Mycobacterial Infections and Therapy)

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