Therapeutic and Microbiological Approaches for Combating Non-tuberculous Mycobacterial Infections

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotic Therapy in Infectious Diseases".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 4197

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Guest Editor
Departament de Fonaments Clínics, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, c/Casanova 143, 08036 Barcelona, Spain
Interests: mycobacterial infections; non-tuberculous mycobacteria (NTM) drug resistance; NTM treatment; NTM epidemiology; NTM microbiology

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Guest Editor
Departament de Fonaments Clínics, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, c/Casanova 143, 08036 Barcelona, Spain
Interests: mycobacterial infections; non tuberculous mycobacteria (NTM) drug resistance; NTM treatment; NTM epidemiology; NTM microbiology; tuberculosis

Special Issue Information

Dear Colleagues,

The incidence of non-tuberculous mycobacterial (NTM) infections is increasing in many countries, even surpassing tuberculosis (TB). Pulmonary disease (PD) is the most important clinical presentation, especially in people suffering with chronic diseases such as bronchiectasis or chronic obstructive pulmonary disease (COPD). Although more than 160 species have been described, most NTM-PD cases are caused by the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB). The backbone of the treatment is based on regimens including macrolides. Additionally, at least three drugs are administered for 18-24 months. The current therapeutical options are limited to 4-5 drugs, such as amikacin, rifamycins, ethambutol, tigecycline, imipenem cefoxitin and linezolid. However, some cases do not respond to treatment, and relapse occurs in more than 10% of MAC and in at least 50% of MAB infections. Drug susceptibility testing (DST) shows resistance for many drugs, such as beta-lactams, tetracyclines, aminoglycosides and others. Moreover, sometimes there is a discordance between in vitro susceptible results and the clinical response and outcome. Drug resistance can be due to intrinsic factors, such as impermeability and efflux pumps, or acquired due to target mutations or other complementary causes. Drug tolerance can result in difficulties reaching the target. For example, this can be due to the intracellular environment, vascular hypoperfusion, or the hypersecretion of mucus and production of biofilm.

It is common to adapt and study TB drugs in NTM. However, they are not always active, and the activity levels can be different given that several bactericidal drugs against TB are bacteriostatic in NTM. There is an urgent need for new compounds with anti-mycobacterial activity and for the study of new combinations, including new and existing drugs. For instance, in recent years, the combination of betalactamase inhibitors with cephalosporines or carbapenems has demonstrated synergistic activity. Other strategies, such as inhaled nitric oxid (NO) or the use of specific phages, should be potentiated. Mucus and biofilm act as barriers to access the mycobacterial cells, requiring minimum inhibitory concentrations (MICs) several folds higher. The treatment should potentiate alternative routes of administration, such as inhalation and the use of compounds that dissolve mucus and biofilm, in order to help antibiotics to reach their targets.

There is also a need to find biomarkers to distinguish who should be treated, and predict the outcome, relapse and mortality as well as, in the near future, design personalized treatments according to the individual characteristics of each patient

Prof. Dr. Julia Gonzalez-Martin
Prof. Dr. Griselda Tudó
Guest Editors

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Keywords

  • mycobacterial infections
  • non-tuberculous mycobacteria (NTM) drug resistance
  • NTM treatment
  • NTM epidemiology
  • NTM microbiology

Published Papers (4 papers)

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Research

14 pages, 1484 KiB  
Article
Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases
by Markus Lang, Uday S. Ganapathy, Rana Abdelaziz, Thomas Dick and Adrian Richter
Antibiotics 2024, 13(5), 404; https://doi.org/10.3390/antibiotics13050404 - 28 Apr 2024
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Abstract
This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural [...] Read more.
This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural diversity and previously described activity against mycobacteria. Bacterial strains, including the M. abscessus complex, M. avium complex, and other clinically relevant NTM, were cultured and subjected to growth inhibition assays. The results demonstrate significant activity against the most common NTM pathogens from the M. abscessus and M. avium complexes. Variations in activity were observed against other NTM species, with for instance M. ulcerans displaying high susceptibility and M. xenopi and M. simiae resistance to AAPs. Comparative analysis of RNAP β and β′ subunits across mycobacterial species revealed strain-specific polymorphisms, providing insights into differential compound susceptibility. While conservation of target structures was observed, differences in compound activity suggested influences beyond drug–target interactions. This study highlights the potential of AAPs as effective antimycobacterial agents and emphasizes the complex interplay between compound structure, bacterial genetics, and in vitro activity. Full article
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12 pages, 3418 KiB  
Article
Biofilm Development by Mycobacterium avium Complex Clinical Isolates: Effect of Clarithromycin in Ultrastructure
by Arij Akir, Abrar Senhaji-Kacha, Maria Carmen Muñoz-Egea, Jaime Esteban and John Jairo Aguilera-Correa
Antibiotics 2024, 13(3), 263; https://doi.org/10.3390/antibiotics13030263 - 16 Mar 2024
Cited by 1 | Viewed by 860
Abstract
Background: The Mycobacterium avium complex includes the commonest non-tuberculous mycobacteria associated with human infections. These infections have been associated with the production of biofilms in many cases, but there are only a few studies about biofilms produced by the species included in this [...] Read more.
Background: The Mycobacterium avium complex includes the commonest non-tuberculous mycobacteria associated with human infections. These infections have been associated with the production of biofilms in many cases, but there are only a few studies about biofilms produced by the species included in this group. Methods: Three collection strains (M. avium ATCC25291, M. intracellulare ATCC13950, and M. chimaera DSM756), three clinically significant strains (647, 657, and 655), and three clinically non-significant ones (717, 505, and 575) of each species were included. The clinical significance of the clinical isolates was established according to the internationally accepted criteria. The biofilm ultrastructure was studied by Confocal-Laser Scanning Microscopy by using BacLight Live–Dead and Nile Red stains. The viability, covered surface, height, and relative autofluorescence were measured in several images/strain. The effect of clarithromycin was studied by using the technique described by Muñoz-Egea et al. with modifications regarding incubation time. The study included clarithromycin in the culture medium at a concentration achievable in the lungs (11.3 mg/L), using one row of wells as the control without antibiotics. The bacterial viability inside the biofilm is expressed as a percentage of viable cells. The differences between the different parameters of the biofilm ultrastructure were analyzed by using the Kruskal–Wallis test. The correlation between bacterial viability in the biofilm and treatment time was evaluated by using Spearman’s rank correlation coefficient (ρ). Results: The strains showed differences between them with all the studied parameters, but neither a species-specific pattern nor a clinical-significance-specific pattern were detected. For the effect of clarithromycin, the viability of the bacteria contained in the biofilm was inversely proportional to the exposure time of the biofilm (ρ > −0.3; p-value < 0.05), excluding two M. chimaera strains (M. chimaera DSM756 and 575), which showed a weak positive correlation with treatment time (0.2 < ρ < 0.39; p-value < 0.05). Curiously, despite a clarithromycin treatment of 216 h, the percentage of the biofilm viability of the strains evaluated here was not less than 40% at best (M. avium 717). Conclusions: All the M. avium complex strains studied can form biofilm in vitro, but the ultrastructural characteristics between them suggest that these are strain-specific characteristics unrelated to the species or the clinical significance. The clarithromycin effect on MAC species is biofilm-age/time-of-treatment-dependent and appears to be strain-specific while being independent of the clinical significance of the strain. Full article
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15 pages, 2446 KiB  
Article
In Vitro Effect of Three-Antibiotic Combinations plus Potential Antibiofilm Agents against Biofilm-Producing Mycobacterium avium and Mycobacterium intracellulare Clinical Isolates
by Sara Batista, Mariana Fernandez-Pittol, Lorena San Nicolás, Diego Martínez, Marc Rubio, Montserrat Garrigo, Jordi Vila, Griselda Tudó and Julian González-Martin
Antibiotics 2023, 12(9), 1409; https://doi.org/10.3390/antibiotics12091409 - 6 Sep 2023
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Abstract
Patients with chronic pulmonary diseases infected by Mycobacterium avium complex (MAC) often develop complications and suffer from treatment failure due to biofilm formation. There is a lack of correlation between in vitro susceptibility tests and the treatment of clinical isolates producing biofilm. We [...] Read more.
Patients with chronic pulmonary diseases infected by Mycobacterium avium complex (MAC) often develop complications and suffer from treatment failure due to biofilm formation. There is a lack of correlation between in vitro susceptibility tests and the treatment of clinical isolates producing biofilm. We performed susceptibility tests of 10 different three-drug combinations, including two recommended in the guidelines, in biofilm forms of eight MAC clinical isolates. Biofilm developed in the eight isolates following incubation of the inoculum for 3 weeks. Then, the biofilm was treated with three-drug combinations with and without the addition of potential antibiofilm agents (PAAs). Biofilm bactericidal concentrations (BBCs) were determined using the Vizion lector system. All selected drug combinations showed synergistic activity, reducing BBC values compared to those treated with single drugs, but BBC values remained high enough to treat patients. However, with the addition of PAAs, the BBCs steadily decreased, achieving similar values to the combinations in planktonic forms and showing synergistic activity in all the combinations and in both species. In conclusion, three-drug combinations with PAAs showed synergistic activity in biofilm forms of MAC isolates. Our results suggest the need for clinical studies introducing PAAs combined with antibiotics for the treatment of patients with pulmonary diseases infected by MAC. Full article
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9 pages, 1140 KiB  
Communication
Antimycobacterial Activity of Hedeoma drummondii against Mycobacterium tuberculosis and Non-Tuberculous Mycobacteria
by Carmen Molina-Torres, Carlos Pedraza-Rodríguez, Lucio Vera-Cabrera, Jorge Ocampo-Candiani, Catalina Rivas-Morales and Ezequiel Viveros-Valdez
Antibiotics 2023, 12(5), 833; https://doi.org/10.3390/antibiotics12050833 - 29 Apr 2023
Viewed by 1357
Abstract
Tuberculosis (TB) remains a major health problem worldwide, and the emergence of multi-resistant strains to first-line drugs has become the biggest obstacle to its treatment. On the other hand, the incidence of non-tuberculous mycobacteria (NTM) in humans has increased remarkably in recent years. [...] Read more.
Tuberculosis (TB) remains a major health problem worldwide, and the emergence of multi-resistant strains to first-line drugs has become the biggest obstacle to its treatment. On the other hand, the incidence of non-tuberculous mycobacteria (NTM) in humans has increased remarkably in recent years. The search for new and better treatments against mycobacterial infections is a constant at the global level. Hence, in this study, we propose to investigate the antimycobacterial effect of the extracts and major compounds of Hedeoma drummondii against clinical isolates of Mycobacterium tuberculosis and non-tuberculous mycobacteria: M. abscessus, M. fortuitum, M. intracellulare, and M. gordonae. To determine the antimycobacterial activity, a microdilution assay was used to establish the minimum inhibitory concentration (MIC) of the different strains of Mycobacterium. The methanolic extract presented the best activity against M. tuberculosis, inhibiting ten of the twelve strains analyzed at a concentration < 2500 µg/mL; meanwhile, the hexanic extract presented the best activity against non-tuberculous mycobacteria (NTM) by inhibiting eight of the ten strains studied at ≤625 µg/mL. Moreover, there is a strong positive correlation between the antimycobacterial activity of pulegone and the hexanic extract against non-tuberculous strains, so this compound could serve as a predictability marker against these types of microorganisms. Full article
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