Targeting antibiotic resistance mechanisms in Mycobacterium tuberculosis: recharging the old magic bullets

“It's clear now that the current ‘magic bullets’ are losing their magic power.”

Tuberculosis (TB) is an ancient disease. This ‘White Plague’ came and went throughout the history of mankind as unavoidable visits from Death until the recent era of antibiotics, starting some 80 years ago. The discovery of these ‘magic bullets’ brought a sudden great victory to our battle against the TB etiological agent, Mycobacterium tuberculosis [1]. Thanks to these powerful chemicals, TB has become a curable disease. Although it remains one of the most difficult infections to treat, the current Direct Observed Treatment Short regimen, which usually takes 6–9 months of continuous chemo-therapy, is quite effective in treatment of drug-susceptible TB. The arising problem now lies in the emergence and wide spread of drug-resistant forms of the disease. Mutations in drug target genes have contributed to the evolution of M. tuberculosis strains that are resistant to the handful of currently available first- and second-line TB antibiotics [2,3]. Repeated misuse of these few drugs has led to the sequential accumulation of the mutations that result in the emergence of strains simultaneously resistant to multiple existing TB drugs. These multidrug resistant, extensively drug-resistant, and most recently totally drug-resistant M. tuberculosis strains pose a serious threat to public health if alternative therapeutic options do not quickly become available [4,5]. It's clear now that the current ‘magic bullets’ are losing their magic power. What are we going to do to contain these multidrug resistant, extensively drug-resistant and totally drug-resistant M. tuberculosis strains?

The search for new magic bullets

The most straightforward pathway to deal with antibiotic resistance has been to search for completely novel classes of drugs that are not affected by existing resistance mechanisms. This strategy has been practiced since the flourishing period (1940s–1950s) of the antibiotic industry during which many new and effective antibiotics were discovered and rapidly introduced to the clinic by fast growing pharmaceutical companies. Things have changed since then. Exhaustion of producing organisms, loss of interest from pharmaceutical companies due to lower profits, and stricter regulations from governments and others are all making new anti-infective drug development a long drawn-out process. Today, it takes on average 12–15 years and half a billion US dollars to bring a new drug from the laboratory to the market [6]. Yet, resistant organisms often appear within 2–3 years after a new antibiotic is introduced [7]. Even if the industry were at the peak of its research and discovery power, it would hardly outrun the efficacy loss of existing drugs due to new resistant forms.

This trend of anti-infective drug development is best exemplified in the case of TB. Right after the paramount discovery of streptomycin in 1943, several other effective TB drugs were introduced, either to replace or supplement the existing inactivated drugs. But one after another, streptomycin, para-aminosalicylic acid, isoniazid, pyrazinamide, rifampicin, ethambutol and others were all defeated by resistant strains of M. tuberculosis. While the efficacy of these drugs was rapidly deteriorating, the antibiotic industry also started its downturn. No new class of TB drug has been introduced for the last 50 years. However, with the alarming worldwide epidemic of drug-resistant TB forms, efforts have been refreshed and there are currently dozens of compounds being tested at various stages of development. It is hoped that TMC207, a truly novel anti-TB compound, will be submitted to the US FDA and the EMA for approval this year [8,101].

“...the bacterial resistome does not seem to be restricted to any class of chemicals on earth...”

Clearly, continued efforts in development and implementation of new classes of antibiotics are essential for tackling drug-resistant TB. But this is not enough. Even if many new drugs were soon to be approved, the emergence of new resistance mechanisms that weaken their activities is inevitable. Indeed, the bacterial resistome does not seem to be restricted to any class of chemicals on earth [9,10]; that is, there would be no drugs that are invincible to pathogenic bacteria in general, M. tuberculosis in particular. Therefore, it is also essential that novel complementary methods, which protect these new drugs from efficacy loss, be continuously developed. These interventions are required to ensure a prolonged lifespan for new drugs after they are implemented.

Recharging the old magic bullets

Another potential pathway to help combat antibiotic resistance is to explore possibilities to recharge the inactive drugs. This approach could be applied both to reactivate drugs that were inactivated by resistance mechanisms, and to improve efficacy of all currently used and upcoming drugs. The strategy includes two alternative directions: chemical optimization that allows inactivated drugs to escape resistance mechanisms, or targeting resistance in which resistance mechanisms are counterattacked by specific inhibitors that (re)sensitize resistant bacteria to the inactive drugs.

Chemical optimization

Chemical derivation using semisynthesis or total synthesis has been successfully used for eluding resistance mechanisms or improving efficacy of available drugs against M. tuberculosis. From the original rifamycins, which were isolated from Amycolatopsis rifamycinica in 1957, a series of derivatives have been produced using chemical modifications. While the prototypic rifamycins B and S have mild antibacterial activity, their synthetic derivatives rifampicin, rifabutin and rifapentine are among the most potent TB drugs. Approximately a third of rifampicin-resistant M. tuberculosis isolates remain susceptible to rifabutin [11,12], whereas rifapentine has a four-times longer half-life than rifampicin in the human body [13]. Another example is the chemical modification of the fluoroquinolone antibiotic family. From nalidixic acid, discovered in 1962, which was quickly inactivated by resistant M. tuberculosis strains, many generations of fluoroquinolones have been generated using diverse chemical modifications [14]. These new fluoroquinolones display not only higher anti-TB activity but also gradually reduced resistance rates compared with nalidixic acid [15]. Indeed, chemical optimization has become an important part of drug development against resistant infections. To successfully defeat the current challenge of antibiotic-resistant TB, this approach should be further investigated. Efforts should be expanded to old, abandoned and rejected antibiotics, as well as antibiotics currently used for other infections but inactive against M. tuberculosis. With more comprehensive endeavors in research and development, reinforced by both governments and the private sector, this approach might transform useless chemicals to potent TB drugs.

Targeting resistance

A promising but not yet fully explored solution, which has recently attracted widespread support from the scientific community, is presented by the concept of ‘targeting resistance’ in which specific inhibitors are used to counteract resistance mechanisms, thereby sensitizing resistant organisms to the inactivated drugs [16]. Perhaps, this is the most direct approach among the three solutions discussed here because it confronts the antibiotic resistance mechanisms per se, rather than to avoid them like the other two methods. This approach has been used to rescue β-lactam antibiotics for the last 30 years. Inhibitors are coadministered to inactivate β-lactamases that are the key resistance mechanism against β-lactams. Thanks to this powerful method, β-lactams have remained active against many bacterial infections in the face of β-lactamases. Importantly, a recent study showed that the β-lactam meropenem coadministered with the β-lactamase inhibitor clavulanate effectively kills not only drug-resistant M. tuberculosis strains but also the bacillus growing in anaerobic conditions, indicating possible potency against latent TB [17]. This work has strengthened the emerging idea that many old, inactive and disregarded antibiotics could be repurposed or recharged to use in TB treatment. Indeed, inhibitors of the intrinsic ethionamide resistance mechanism were shown to increase susceptibility of M. tuberculosis to this highly toxic drug [18,19]. These inhibitors might help to promote the use of ethionamide in TB treatment. This approach might also be applicable to many well-known drug resistance mechanisms of M. tuberculosis described elsewhere in this special issue of Expert Review of Anti-Infective Therapy.

“Besides the traditional approach of searching for new drugs, multiple other methods will need to be considered in parallel.”

In summary, the worsening epidemic of drug-resistant M. tuberculosis strains is a serious threat to humans, and we need to act now to halt the spread of these deadly bacteria. Besides the traditional approach of searching for new drugs, multiple other methods will need to be considered in parallel. For example, studies of novel drug combinations, pharmacodynamics and pharmacokinetics will help to optimize the current regimens. We also need to re-examine the anti-TB activity of already available, clinically-approved antibiotics. Methods for recharging inactivated antibiotics are essential to prolong the life span of available drugs or to rescue those inactivated by resistant M. tuberculosis strains.

Biography

Liem Nguyen