|Year : 2019 | Volume
| Issue : 1 | Page : 7-21
Antimycobacterial strategies to evade antimicrobial resistance in the nontuberculous mycobacteria
Beverley Cherie Millar, John Edmund Moore
Department of Bacteriology, Northern Ireland Public Health Laboratory, Belfast City Hospital; Centre for Experimental Medicine, Queen's University; School of Biomedical Sciences, Ulster University, Northern Ireland, UK
|Date of Web Publication||12-Mar-2019|
Beverley Cherie Millar
Department of Bacteriology, Northern Ireland Public Health Laboratory, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AD, Northern Ireland
Source of Support: None, Conflict of Interest: None
The nontuberculous mycobacteria (NTM) have recently emerged as important bacterial pathogens of both animals and humans. Of particular, concern is the high level of antimicrobial resistance (AMR) displayed by these organisms, which complicates treatment and potential successful outcomes. This review, therefore, wishes to examine novel compounds and approaches to combatting AMR in the NTMs, specifically examining antimycobacterial (NTM) compounds from plants and venoms, as well as examining synergistic and combination effects with other antimicrobials. Novel and modified drugs including new inhaled drugs are examined, as well as the repurposing of existing drugs for antimycobacterial activity. Many of these novel interventions are at various stages of development, from initial concept through to licensed intervention. The challenge remains to translate these interventions from in vitro laboratory models to effective in vivo interactions. When these are realized, then we will have the opportunity of overcoming NTM AMR, to the benefit of medicine, society, and humanity.
Keywords: Antibiotic resistance, antimicrobial resistance, cystic fibrosis, nitric oxide, non-tuberculous mycobacteria, nontuberculous mycobacteria
|How to cite this article:|
Millar BC, Moore JE. Antimycobacterial strategies to evade antimicrobial resistance in the nontuberculous mycobacteria. Int J Mycobacteriol 2019;8:7-21
|How to cite this URL:|
Millar BC, Moore JE. Antimycobacterial strategies to evade antimicrobial resistance in the nontuberculous mycobacteria. Int J Mycobacteriol [serial online] 2019 [cited 2019 Mar 21];8:7-21. Available from: http://www.ijmyco.org/text.asp?2019/8/1/7/253951
| Introduction|| |
Recently, the nontuberculous mycobacteria (NTMs) have emerged as important human and veterinary pathogens, particularly in respiratory disease. These organisms, sometimes referred to as the atypical mycobacteria or “Mycobacteria Other Than Tuberculosis”, are usually found in water, soil, and other environmental sources and are those mycobacteria which do neither belong to the Mycobacterium tuberculosis complex nor are Mycobacterium leprae. At present, there are 198 species (including synonyms) of Mycobacterium, with standing in nomenclature (http://www.bacterio.net/mycobacterium.html), of which the majority belong to the NTMs. Several key seminal review publications describing NTMs have comprehensively reviewed various aspects of NTM disease pathophysiology, epidemiology, diagnosis, treatment, and clinical management and we guide readers to these sources of information.,,
To date, none of these recent review publications have addressed novel strategies to overcome antimicrobial resistance (AMR) among the NTM organisms, and hence, it was the aim of this review to examine recent developments in overcoming AMR in NTM organisms.
| Antimicrobial Resistance|| |
One aspect to emerge from these publications is that of AMR with the NTM organisms. AMR has now emerged as a global public health crisis, with a variety of organisms, namely the Enterobacteriaceae, Pseudomonas aeruginosa and the mycobacteria, particularly TB., AMR in bacteria may be manifested through several mechanisms, including alteration in cell wall permeability to antibiotics, enzymic degradation of antibiotics, efflux pump mechanisms, mutation in protein synthesis and the organism's ability to uncoil its nucleic acid. [Table 1] summarizes the resistance mechanisms that NTM organisms adopt to evade attack from conventional antibiotic agents.
|Table 1: Action and resistance mechanisms of major classes of conventional antibiotics used to treat nontuberculous mycobacterias|
Click here to view
Given that the NTM organisms are environmental, it is not surprising that they have developed highly elaborate mechanisms of AMR. The environment, particularly the rhizosphere, is a harsh environment for NTMs to survive, due to highly complex inter-strain, inter-species, and inter-genus competition for habitat and nutrition. Therefore, it is advantageous that any organism can ideally perform two important functions in such a scenario, namely (i). evolve AMR mechanisms to evade natural antibiotics being excreted as secondary metabolites by neighboring bacteria, as well as (ii) having the ability to excrete novel natural antibiotic and/or antibiotic-like compounds, to suppress the growth and proliferation of neighbor bacterial organisms. While the NTMs are highly evolved in relation to developing AMR mechanisms, their ability to produce novel antimicrobial compounds is limited whereas paradoxically, another soil organisms, Streptomyces spp., are highly developed in producing novel antimicrobial compounds, but lack sophisticated AMR mechanisms, to evade natural antimicrobials from their neighbors in the soil.
| Mechanisms to Combat Antimicrobial Resistance in Nontuberculous Mycobacteria|| |
The aim of this review is to highlight recent developments which have appeared in the scientific literature within the last 2 years (2017–2018), examining a variety of approaches targeting NTMs.,,,
Medicinal plants are a source of bioactive compounds that can be effective treatments of various diseases globally. Many countries, particularly Mexico, India, Iran, Turkey, and Africa, have a wealth of medicinal plant species which have had a long standing in traditional medicine approaches to the treatment and management of diseases including tuberculosis. Ethnobotanical/pharmacological studies relating of the use of such plants in conjunction with polyherbal medicines, traditionally used for the treatment of tuberculosis are forming the foundations for the identification and in vitro examination of antibacterial properties against NTMs [Table 2].
|Table 2: Pharmacognosy relating to the antimycobacterial activity of plant extracts|
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Animal venoms from snakes (terrestrial and sea), scorpions, spiders, honey bees, wasps, and snails, have been investigated and found to be a rich source of natural antimicrobial substances including proteins, amines, bioactive peptides, antimicrobial peptide (AMP), toxins and enzymes, showing activity, by a number of different mechanisms, against many pathogens and more recently, NTMs [Table 3].
Of particular, clinical interest has been the AMPS which are short (10–15 amino acid residues), due to the fact that they are structurally stable, do not easily induce AMR compared to conventional antimicrobials and have shown potent potential in killing bacteria, fungi, viruses, and parasites. AMPs are currently a source of therapeutic potential particularly as they are devoid of hemolytic properties, not toxic to host cells and may be readily synthesized and modified.
Owing to the intrinsic resistance of NTMs to most commonly used antibiotics, such infections are treated by a multidrug regimen as highlighted in the recent “British Thoracic Society Guidelines for the management of non-tuberculous mycobacterial pulmonary disease,” however, treatment issues are further complicated by the ability of Mycobacterium abscessus to develop macrolide resistance on exposure to sub-inhibitory concentrations of the drug  or where other members of the macrolides are used, such as in the case of low-dose azithromycin in the management of patients with cystic fibrosis (CF). Currently, screening for synergistic interactions of approved drugs is an approach which has identified novel in vitro synergistic combinations, with one of the largest studies totaling 180 dual drug combinations against M. abscessus, reported recently by Aziz et al. 2018. [Table 4] summarize several studies which report on potential synergistic and combination effects with other antimicrobials.
|Table 4: Potential synergistic and combination effects with other antimicrobials|
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Of interest, has been a recent publication examining the interaction between spices and antibiotic resistance in M. abscessus. In this study, M. abscessus isolates (n = 9 multidrug-resistant clinical isolates from CF patients + 1 reference strain) were examined for their direct susceptibility to 27 spices, as well as the interactive effect of this spice combination to their susceptibility to amikacin and linezolid antibiotic, with standard disk diffusion assay. Five isolates of M. abscessus (5/10; 50%) failed to grow on the spice enriched medium, which included four clinical isolates and the National Culture Type CollectionReference Strain. Of the remaining five isolates which grew on the spice medium, no cultural phenotypic differences were observed, compared to unsupplemented controls. In the case of both amikacin and linezolid, the zone of inhibition increased with the inclusion of the spices. Initially, all isolates of M. abscessus were fully resistant to linezolid (mean zone of inhibition = 0 mm), and growth was to the edge of the antibiotic disk, whereas when in the presence of spices, large zones of inhibition were observed (mean zone of inhibition = 33.3 mm). With amikacin, the mean zone of inhibition increased from 23.2 mm to 32.0 mm, in the presence of spices. These data suggest that the spices were interacting synergistically with the antibiotics, thus making the antibiotic more potent against the bacteria tested. This study is significant as it demonstrates a positive interaction between spices and the conventional antimycobacterial antibiotics, amikacin, and linezolid. Given the burden of AMR to M. abscessus, particularly in a patient with chronic disease such as CF, any food-related innovation that can help maximize the potency of existing antimycobacterial antibiotics is to be encouraged and developed. The specific mechanism as to how spices increase the potency of such antibiotics with M. abscessus now needs to be elucidated, as well as novel food (spice) delivery modalities developed, including novel medicinal foodstuffs or functional foods, that can harness this beneficial effect in vivo.
Due to the urgent need to address the AMR of NTMs, it is important to discover new antimycobacterials, however to date, such drug discovery has been limited, particularly in relation to progression of such novel drugs to clinical trials [Table 5].
|Table 5: The antimycobacterial activity of novel drugs/compounds and modified drugs|
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Of particular, interest has been the development of a novel inhaled nonantibiotic therapy, nitric oxide gas formulation, Thiolanox ® (Novoteris, Garden Grove, CA., USA), for the treatment of CF and which is currently in Phase II development (NCT02498535). Interestingly, in Phase I of the clinical study, with CF patients, 160ppm NO inhaled for 30 min, three times daily for five days over two consecutive weeks, indicated that this therapy was safe and significantly reduced the number of various bacteria including M. abscessus, which consequently reduced pulmonary inflammation and increased lung function to levels not commonly observed after antibiotic therapy  [Table 6]. It has been suggested that NO has a multiplicity of targets that are non-organism specific, attributed to its oxidative and nitrosylating effects. NO eradicates microbes by nitrosylating their heme-or thiol-containing essential metabolic proteins which interfere with RNA replication and DNA repair mechanisms, which in turn damages cellular structure and function and modulates the host immune response. Subsequently, an interventional clinical trial is currently in progress to investigate if NO therapy can reduce the NTM bacterial load in the lungs of adults and adolescents with NTM infection (NCT03331445), the preliminary results of which are summarized in [Table 6]. Furthermore, the antibacterial efficacy of a biopolymer, NO-donor BIOC51 (Vast Therapeutics, Chapel Hill, NC., USA) has been demonstrated against NTMs in a mouse in vitro and in vivo model.
|Table 6: Novel Inhaled therapies examined for treatment of nontuberculous mycobacterias|
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It is important to consider the fact that NTM can exist both extracellularly in biofilms and intracellularly within macrophages and other host cells, where they can replicate intracellularly. This promotes a challenge when delivering antimicrobial therapy at concentrations which would be effective against NTMs persisting either within biofilms or intracellularly within host cells. Of significant interest has been the development of a liposomal amikacin formulation to address these issues and in particular liposomal inhalation suspension which can be delivered by to target NTM lung diseases. Such delivery mechanisms ensure the delivery of high concentrations of antibiotic directly to the lung along with low systemic concentration in an attempt to prevent cytotoxicity. In vitro and in vivo animal models have shown the ability which this liposomal inhalation suspension has in penetrating NTM biofilms, as well as enhancing amikacin uptake into macrophages. Of major clinical interest has been a multi-centered clinical trial (NCT02344004) which concluded that a single daily nebulization of amikacin liposome inhalation suspension (590 mg), when added to standard guideline-based therapy (GBT) in patients with refractory Mycobacterium avium complex (MAC) lung disease, achieved significantly greater culture conversion by month 6 (defined as three MAC-negative sputum cultures) than GBT alone, along with comparable rates of serious adverse events. These findings further highlight the importance of novel inhaled therapeutic approaches for the treatment of MAC lung disease.
Another approach to tackle the challenge posed by NTM AMR has been the repurposing of existing drugs, namely those that had been approved previously for the treatment of tuberculosis, such as bedaquiline, clofazimine, rifabutin and skin infections, such as tedizolid [Table 7]. Of concern, however, is that fact the resistance mechanisms associated with the MmpL family of proteins have been identified in M. abscessus, in the case of clofazimine and bedaquiline, where clofazimine-resistant strains demonstrated cross resistance to bedaquiline.,,
In addition, in vitro, the antimicrobial effect on NTMs as a result of polypharmacy for the treatment of noninfective conditions has been noted and opens up another avenue to peruse [Table 7].
[Table 8] highlights a number of other approaches which have been investigated in the search for antimycobacterial drugs for NTMs including the examination of existing screening libraries and the examination of bacterial virulence and pathogenic mechanisms with the potential to develop antivirulence therapies and bacteriophage therapy.
Bacteriophage therapy is an interesting approach to consider in the fight against AMR, however to date research in the potential use of such therapy in the case of NTM has been limited with recent focus associated with M. tuberculosis. Indeed, phage therapy although extensively used in Eastern Europe in relation to other pathogenic organisms, is limited elsewhere globally. In general clinical trials, in relation to phage therapy, have been sparse, primarily due to safety concerns relating to the sterility and purity of phages and the potential onset of toxic shock due to the bactericidal effect of phages. Furthermore, regulatory guidelines relating to their therapeutic use require clarification.
In conclusion, AMR in NTM organisms presents significant clinical treatment dilemmas and challenges, for a range of infections associated with NTMs. This review presents a synthesis of novel and innovative approaches, as described in [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], in an attempt to circumvent such AMR problems. These approaches are at various stages of development, from initial concept through to licensed intervention. The challenge remains to translate these interventions from in vitro laboratory models to effective in vivo interactions. When these are realized, then we will have the opportunity of overcoming NTM AMR, to the benefit of medicine, society, and humanity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]