Bridging Eras: integrating ancient remedies with modern biotechnology to combat Non-TB skin infections

The rising global concern of antibiotic resistance has renewed scientific interest in understanding and exploring the traditional remedies as alternative or complementary therapeutics. Ancient medical systems such as Ayurveda have used plant-based systems such as Neem, turmeric for their anti-inflammatory, antimicrobial and/or wound healing actions. Non-tuberculosis mycobacteria (NTM), a diverse group of mycobacterial species excluding Mycobacterium tuberculosis, are increasingly recognised as important causes of chronic skin and soft tissue infections. These infections are specifically challenging as the NTM species often invade deeper layers of the skin, exhibiting high levels of intrinsic antibiotic resistance and are frequently difficult to diagnose in early stages of infections. As a result of this, treatment failures are often, and hence there is a growing interest in sustainable, natural and less toxic treatment options. This leads to the need for scientifically backed ancient knowledge as a potential solution for these kinds of infections. Modern biotechnology could provide innovative ways to enhance the clinical utility of such natural or ancient compounds by addressing the limitations, like poor solubility, low stability and restricted tissue penetration. Modern biotechnology could enhance bioavailability and allow controlled as well as targeted release at infected sites. Therefore, the integration of traditional or ancient plant-derived therapeutics with advanced biotechnology holds a significant promise for developing safer, more effective and sustainable treatment approaches against NTM-related skin infections. The upcoming part hence focuses on bridging ancient remedies with modern biotechnology for their combined potential advantages and some real-life applications with prospects with regard to the management of non-TB mycobacterial skin infections.

1 Introduction

The alarming rise in antibiotic resistance has led to many global health challenges that need to be addressed by the scientific community. This has urged the scientific community to work on innovative and sustainable solutions (Chinemerem Nwobodo et al., 2022). One promising but underexplored solution could be offered by the utilisation of ancient medicinal systems, such as Ayurveda and Chinese medicine, as well as other indigenous practices (Díaz-Guerrero et al., 2025). These systems have been used for centuries, and the extract of certain plants like Neem (Azadirachta indica) and Aloe vera has shown great anti-microbial and anti-inflammatory effects (Shobha, 2020). The ancient systems hold a rich history of natural remedies, some of which are not utilized to their full potential. Some of the remedies have not even been tested with modern science. Moreover, bridging ancient knowledge with modern technologies like biotechnology can provide better insights into them while increasing their efficacy and applications.

Tuberculosis (TB), caused by the M. tuberculosis, is one of the most infectious diseases worldwide (Okram and Singh, 2024). The rise in antibiotic resistance has led to severe problems in the treatment of TB, as the pathogen has gained resistance to many commonly used antibiotics (Serajian et al., 2025). The primary pathogen/s responsible for the disease fall under the genus of Mycobacterium. The problem of antibiotic resistance against M. tuberculosis is widely being tackled by the scientific community (Serajian et al., 2025; Aggarwal et al., 2024). However, a lesser-known but increasingly relevant group of bacteria within the genus of Mycobacterium is the non-tuberculosis mycobacteria (NTM) (Wamalwa et al., 2024). In contrast to TB, where there is a single primary responsible pathogen, M. tuberculosis, which falls under the category of the M. tuberculosis complex, the NTM comprises a diverse group of mycobacterial species that are not part of the M. tuberculosis complex (Vahabi et al., 2024; Porvaznik et al., 2016). These organisms are capable of causing chronic skin infections, especially in people with compromised immunity. Recent studies have demonstrated that cases of NTM infections are on the rise, especially those that infect the skin and soft tissues. These incidences are more common in people undergoing treatments like chemotherapy, organ transplant, or anything that leads to compromised immunity (Li et al., 2017). Also, the outbreak of cutaneous NTM infections is rising in people going through cosmetic surgeries or tattooing, etc (Ma et al., 2024). Unlike M. tuberculosis, NTM infections are not spread from human-to-human contact, but rather the spread is more concerned with environmental exposure. One of the other means by which this infection spreads in contaminated water sources is that it can also spread through contaminated water, instruments, and other means, making the spread of these infections insidious in community settings like hospitals (Li et al., 2017; Gan et al., 2025). The manifestation of skin-related infections is broad, including abscesses, ulcers, and complex issues like sporotrichoid spread. Another complicated issue with these infections is that they are frequently misdiagnosed or diagnosed very late due to the slow-growing nature of NTM (George, 2023).

Diagnosis and treatment of NTM skin infection pose significant challenges, unlike M tuberculosis, in which standardized diagnostic and treatment protocols are developed and often followed. Many of the NTM species have shown resistance to conventional antibiotic treatments, and they also possess the ability to form biofilms, which further makes it even more challenging to develop diagnostics and treatment against NTM infections (Saxena et al., 2021). This reduces the effectiveness of available antibiotic treatments, hence resulting in persistent and recurring infections. Due to these limitations, there is a growing need for sustainable and alternative therapeutic strategies. The ancient medical systems could be one of the best sustainable alternatives. These systems provide us with large numbers of natural compounds that have shown anti-inflammatory, antimicrobial, and wound-healing properties. But, the source of these compounds is plants in most cases, and these natural compounds have certain characteristics that make them hard to use for treatments. These include low water solubility, low bioavailability, low stability, as well as low penetration (Zhang et al., 2022; Sideek et al., 2022) in particular cases where it is required, like in skin or soft tissue infections. This is where modern biotechnology can provide significant value to overcome these limitations. Modern biotechnology techniques like nanoencapsulation, liposomal delivery systems could help us improve stability and bioavailability. These modern techniques not only help improve stability and availability but also decrease potential toxicity (Nsairat et al., 2023; Singh et al., 2019).

Hence, integration between ancient plant-based remedies and modern biotechnology can provide us with a synergistic and sustainable pathway to manage the drug-resistant NTM infections. This also allows us to meet the global criteria of having eco-friendly and economical (affordable) solutions against NTM infections. Therefore, this review focuses on exploring interdisciplinary diagnostics and therapeutic techniques by understanding and modifying the natural remedies using modern biotechnology.

2 Clinical manifestations and epidemiology of NTM skin infections

Non-tuberculosis mycobacteria (NTM) are bacteria that include all the species of bacteria that are not M. tuberculosis. NTM also excludes the close relatives of M.tubeculosis, such as M. leprae and M.africanum (Haworth et al., 2017). Over 190 species of NTM have been identified. Out of these 190 species, 170 of them have been found to be pathogenic to humans and animals. They cause a wide range of infections out of which the pulmonary infections are most frequent, with a frequency of 65%–90% (Porvaznik et al., 2016; Haworth et al., 2017). But in immunocompromised individuals, these bacteria have been reported to cause skin and soft tissue infections (SSTIs) (Zhou et al., 2025). NTM infections have emerged in recent years (Kumar et al., 2021). Out of which NTM skin and soft tissue infections pose a large number of clinical presentations, this does not include any life-threatening conditions in recent times. But in the future, this might lead to an increased morbidity rate and hence may affect the quality of life (Wang et al., 2023). There have been reports suggesting an increase in NTM skin infections globally (Mei et al., 2019; Gopalaswamy et al., 2020). The contributing factors behind this increase include, increase in people having compromised immunity, an increase in the overall number of cosmetic surgeries, etc (Blakney et al., 2022; Wang et al., 2022). A few of the most concerning contributing factors to the same are increased antibiotic resistance of NTM strains against the antibiotics used and the ability of NTM to survive in the human host under various skin environments (Luo et al., 2021). Certain NTM Species are also known to form biofilms to evade the host’s immune system (Mehta et al., 2024). As these infections have become more common, it is certain for us to understand about various strains of species that are involved in the manifestation of the SSTIs. Different species have different survival strategies and infection mechanisms; hence, it is important to know about specific strains and their symptoms to understand the diagnosis and/or the treatments for NTM skin infections.

NTM are also sometimes called atypical mycobacteria. Many NTM species have been reported to cause SSTIs. They include M. marinum, M. kansasii, M. fortuitum, M. ulcerans, M. abscessus, M. chelonae, etc (Nohrenberg et al., 2023). Out of these, certain species are part of RGM, that is, Rapidly Growing Mycobacteria like M. abscessus, M. fortuitum, M. chelonae, etc (George, 2023). Some of the NTM are also part of the Slow-Growing Mycobacteria (SGM), like M. marinum. Most of these bacteria are slender, non-motile, and in most cases, acid-fast bacilli. Above are some of the most common species of NTM that cause cutaneous or SSTIs, but many other species of NTM can cause the infection. These bacteria are transferred in most cases by contaminated environmental sources like water or contaminated surgical instruments used during cosmetic surgeries like hair transplants. There have been reports of almost no human-to-human spread of this infection with a few exceptions (Misch et al., 2018). Contaminated water out of all these has been identified as one of the major sources behind these outbreaks of skin infections caused by NTM bacteria. These bacteria have a high capability to form biofilms; hence, it has been complicated to develop decontamination techniques against these bacteria. Due to this resistance to standard disinfection techniques in many places, these species have become the source of nosocomial infections (i.e., in hospitals) (Manzoor et al., 1999). Some studies have suggested that cutaneous infections by NTM have risen almost threefold from 1980–1990 to 2000–2009 in Olmsted County (U.S). whereas some studies in China suggested an annual increase in NTM skin infections from 2013 to 2023 (Wentworth et al., 2013). Although the amount of data on NTM spread across the world is limited, this could not be ignored. It is better to act now than later. This is to prevent this problem from becoming a widespread public health concern. As it is said that it is good to have solutions before the problems escalate!.

3 NTM skin infections and available treatments

Symptoms of NTM skin infections could vary depending on the strains that are taking part in the process of infection, the extent of infection, etc. But some of the common symptoms of NTM SSTIs include localized lesions that might appear in the form of small, raised bumps, nodules, or abscesses, inflammation, folliculitis, non-healing wounds, especially at surgical sites, etc (George, 2023). Some other possible symptoms also include fever, fatigue, or weight loss in disseminated NTM skin infections (George, 2023). Skin infections caused by NTM are hard to diagnose as they mimic other clinical conditions, like leprosy, Lupus erythematosus, certain fungal infections (e.g., sporadic mycosis), etc (Zhou et al., 2025; George, 2023). The nonspecific nature of NTM skin infection makes it even harder for clinicians to diagnose NTM skin infections. This also causes problems in the treatment of the NTM infections. Most people realize the skin infection as an NTM skin infection only when other skin infection treatments fail to treat it. Because of this, people are often being treated with the wrong antibiotics or treatment who are suffering from NTM skin infections. This further makes it complicated to treat the NTM skin infections (George, 2023). The common areas that are affected by NTM skin infections include: hands, forearms, and the facial area. Some other areas may also include, abdomen, chest, scalp, etc (Nohrenberg et al., 2023). The occurrence based on location might differ due to certain actions, including surgeries, or any clinical procedures like hair transplants. In very rare cases, the NTM infections might also affect multiple organs in the human system, which is more common in cases having compromised immunity (i.e., patients suffering from HIV, AIDS) (Sharma and Upadhyay, 2020). Timely diagnosis is crucial in the treatment of NTM skin infections. Hence, clinicians should consider NTM skin infections as one of the potential causes while diagnosing a skin condition that might be related to it.

In most cases, NTM skin infections have delayed onsets, as it takes about 2–8 weeks to develop an infection after being exposed to contaminated instruments or the environment. The skin lesions gradually develop and become severe (Fialho et al., 2024). Hence, it is important to diagnose NTM skin infections and give treatment in the right direction. Another challenge posed for diagnosis and treatment is that the type of species involved has differences in the onset of symptoms and hence the severity (George, 2023). Therefore, the treatment would be different depending on the species being identified. Even the affected area of the body varies with the species causing the infection.

3.1 Skin infection with RGM species

Most commonly found RGM species in NTM infection include M. abscessus, M. fortuitum, and M. chelonae. Out of these, M. abscessus is considered one of the most pathogenic RGM species (George, 2023). This also makes it challenging to be dealt with in terms of diagnosis and treatments (George, 2023). Patients undergoing immunosuppressive therapy have shown severe infection by M. abscessus (George, 2023). In most cases, the symptoms of infection by M. abscessus are non-specific and include abscesses, ulcers that are non-healing, etc (George, 2023). Patients having systemic infections have also shown certain manifestations like lymphadenopathy (Su et al., 2013). Table 1 shows patients showing infection of M. abscessus on the scalp after hair transplant. Most cutaneous symptoms are non-specific, like the presence of abscesses and non-healing ulcers, but in severe cases, the patients may suffer from systemic infection (Fialho et al., 2024). With the type of strains or species, symptoms, or factors related to the skin infection changes, for example, M. chelonae is associated with skin infections related to surgical wound traumas and/or water-contaminated cases. This is more common in people suffering from diabetes, who take insulin injections, and the infections are seen at injection sites (Jagadeesan et al., 2018). Symptoms include nodules with sinus discharge, as given in Table 1. In most cases, the treatment involves a combinatorial approach where multiple antibiotics are used to treat the conditions. For M. abscessus, the antibiotics generally used include macrolides, cefoxitin, etc. The antibiotics used against M. chelonae include the use of tobramycin, linezolid, etc (George, 2023).

Table 1

Table 1. Common NTM species causing skin and soft tissue infections (SSTIs) and their clinical characteristics.

3.2 Skin infection with SGM species

Some of the common NTM skin infections include the infections caused by M. marinum, M. ulcerans (George, 2023). This particular species is relatively connected with occupational infections. As it is more common in people working with pets, especially fish. Therefore, in many cases, infections caused by M. marinum are termed as fish-tank or swimming pool granuloma. The symptoms include single or multiple lesions at the site of infection. But in severe cases, the infection might lead to tenosynovitis, arthritis, etc (George, 2023; Van Seymortier et al., 2004). M. ulcerans is considered to infect mostly children and young people. The symptoms include subcutaneous nodules that increase in size over time and may later develop into an ulcer (van der Werf et al., 1999). The infection caused by M. marinum is illustrated in Table 1. These nodules later on may become ulcerated, which could cause soft tissue infection, and could even reach bones if not treated properly with the right methods (George, 2023). The major reason behind this deep penetration is considered to be the production of a lipid mycolactone by the bacteria (George, 2023; Yo et al., 2018). This lipid has certain properties like immunosuppression, cytotoxicity, etc. These properties help the bacteria to invade the host’s immune system and hence penetrate deeper into the skin if not treated on time (Misch et al., 2018).

Treatments with antibiotics are generally provided against the NTM SSTIs. Usually, treatment involving only one antibiotic fails to treat, as the bacteria are highly adaptable and show resistance even during the treatment. Hence, a combination of antibiotics is generally used based on the extent of infection, the species involved, etc., and the effectiveness of the antibiotic treatments varies with the species involved (George, 2023). But in severe cases where the diagnosis of NTM skin infections has been delayed, or the infection has already penetrated deep into the skin, the treatments with antibiotics do not show promising results. Due to some abilities of these NTM bacteria to resist the treatments, like the formation of biofilm (George, 2023).

Therefore, while antibiotics remain one of the most widely used treatments for NTM skin infections. Their efficacy is limited in certain cases, like when the diagnosis is delayed. Hence, looking for alternative and better approaches has become one of the challenges for the scientific community. This also aligns with the fact that the NTM bacteria have high adaptability towards antibiotics. Hence, there is an urgency to come up with alternative, better, and highly efficacious solutions.

4 Alternative therapeutics: natural compounds and biotechnology in NTM management

The increasing resistance of NTM bacteria against commonly used antibiotics makes it even more challenging to develop an alternative and better solution to the NTM SSTIs. In the same context, plant-based natural compounds have gained significant attention due to their natural origin and lower toxicity. Also, they provide a broad spectrum of antimicrobial and wound-healing properties, which could help us overcome antibiotic resistance in a shorter time. Many natural compounds used for their medicinal properties have demonstrated significant antimicrobial activity against mycobacteria, including curcumin, neem, and tea tree oil. Some of these compounds have also shown their ability to modulate the immune system of humans, with their ability to repair the skin in skin-related problems or infections. Compounds such as curcumin have demonstrated antimicrobial effects against certain NTM species like Mycobacterium avium (Wang et al., 2023). In the same regard, the neem extracts have been reported to inhibit the growth of certain mycobacterial strains. Their antimicrobial activities have been checked using chronic skin wound models (Alzohairy, 2016). Many of these natural compounds have also demonstrated their ability to reduce inflammation and heal wounds faster, which could be very useful while treating the NTM skin infections (Liang et al., 2022).

Although being advantageous in terms of their natural origin and low toxicity, these compounds have drawbacks that include lower solubility, a lack of targeted effects, and lower skin penetration. This is where modern biotechnology techniques come in, where they can help overcome these challenges or problems. All these problems need to be solved; only then can these natural compounds be given as standalone therapeutics. To overcome these, many scientists are infusing the biotechnology-based delivery system with these natural compounds. For instance, nanoencapsulation is one such approach in which the compound having medicinal effects is encapsulated in a nano matrix. This results in the protection of the active compounds, with increased absorption, increased bioavailability, and increased stability (Chowdhury et al., 2024). One such example includes the formulation that is a nanoemulgel having curcumin and neem extracts. This further resulted in increased or better stability with enhanced antimicrobial properties (Giri et al., 2024). Some of the other techniques involve a liposome-based delivery system, into which small spherical, microscopic structures (vesicle-like) called liposomes are used to deliver drugs or compounds of interest. These liposomes are made of two layers of lipids that encapsulate the substance or compound inside them. The advantage here is also that the liposomes could be used for target-specific delivery of the active ingredients (Sercombe et al., 2015). The same delivery system could be used to deliver the active ingredients of natural compounds like neem, curcumin, etc. This encapsulation reduces the contact of the active ingredient directly with the skin; therefore, it reduces the skin irritation in topical applications (Singh et al., 2014). One of the best examples of fusion between ancient knowledge and modern biotechnology could be the use of polymeric or silica nanoparticles to deliver azadirachtin and nimbolide, which are the active ingredients in neem. This could result in enhanced antimycobacterial activity of the therapeutics. This would be highly effective against the strains of bacteria that form biofilm (Dhanya et al., 2015). Also, the high-throughput technologies of bioinformatics are continuously being employed to find novel and active ingredients from these natural compounds. This would result in better and safer treatments for NTM skin infections. These techniques can help us find active ingredients that can specifically target cell wall synthesis, biofilm formation, etc., in NTM bacteria (Zhang et al., 2025).

The combination of biotechnology techniques like nanoencapsulation with extracts of natural compounds like neem could provide a promising strategy against tackling the NTM skin infections. Therefore, using natural compounds with the fusion of modern biotechnology could provide us with one of the best alternatives and specific treatments against NTM skin infections. This combinatorial approach promises to give better results with less reliance on conventional antibiotic treatments, hence leading to a better future.

5 Concluding remarks

• NTM skin infections are globally rising and posing a possible global health concern, as these infections are difficult to diagnose and treat due to antibiotic resistance and clinical similarities with other skin conditions.

• Conventional antibiotic treatments have limited success due to high resistance and biofilm-forming strains.

• Natural plant-based compounds like curcumin demonstrate promising antimicrobial and wound healing properties with less toxicity

• Modern biotechnology-based techniques like nanoencapsulation increase the effectiveness and efficacy of these natural compounds.

• In the future combination of these plant-based therapeutics with modern biotechnology could provide with safer and promising alternative to conventional treatments against NTM skin infections.

• Future clinical trials with robust data of these therapeutics is required before real-world applications.

Author contributions

NT: Writing – original draft. KU: Writing – review and editing, Conceptualization, Writing – original draft, Supervision.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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