Counterattacking drug-resistant tuberculosis: molecular strategies and future directions

The increasing omnipresence of drug-resistant forms is making tuberculosis (TB) once again a major public health concern [1]. Factors such as poverty, aging populations, malnutrition and the current epidemic of AIDS, all together, have created an immense pool of individuals vulnerable to drug-resistant TB. More effective therapeutic strategies are urgently needed to contain the rapid spread of drug-resistant strains of Mycobacterium tuberculosis. Alongside the search for completely new classes of anti-tuberculous drugs, an emerging strategy to combat drug-resistant TB is presented by the concept of ‘targeting resistance’, wherein inhibitors of resistance mechanisms are used to potentiate the activity of available drugs [2]. Recent work has suggested that many old, forgotten or abandoned drugs could be used effectively for TB treatment using this potentiating approach. This strategy might provide us with a better solution for the fight against drug-resistant TB. However, much work remains to be done in order to apply these ideas to the clinical treatment of TB in humans.

How practical is this approach? What is the molecular basis of current strategies for anti-tuberculous drug potentiation? In an attempt to bring together many experts in this discussion, the editors hope that this special focus issue of Expert Review of Anti-Infective Therapy will shed light on the molecular mechanisms underlying these therapeutic strategies. The articles in this issue also discuss the feasibility and potential of this approach and point out the future directions in this area of TB research.

The only, yet powerful, example that showcases the clinical applicability of this strategy is the use of β-lactamase inhibitors in potentiating β-lactams. The lifespan of β-lactams in the clinic has been prolonged for the last three decades thanks to the introduction of β-lactamase inhibitors. Otherwise, many of these valuable drugs would have become useless. Despite being the most commonly prescribed class of drugs against bacterial infections, β-lactams had never been seriously considered for use against TB until recently when a study showed that the meropenem/clavulanate combination effectively kills not only drug-resistant but also anaerobically grown M. tuberculosis in vitro, indicating a possible use for treatment of drug-resistant and latent TB [3]. In this issue, Kurz and Bonomo revisit this very topic with a thoughtful review article [4]. They discuss in-depth the question of whether or not β-lactam potentiation by β-lactamase inhibitors could be applied to TB chemotherapy. From the analysis of these experts, the M. tuberculosis major β-lactamase appears to be a susceptible target for future development of effective TB-specific combinations of β-lactams with β-lactamase inhibitors. Despite a few obstacles potentially hampering the application of these agents for TB treatment, the authors’ discussion positively points out that these problems are surmountable.

This potentiating approach has also been investigated with ethionamide, the second-line drug that is commonly used to treat M. tuberculosis strains resistant to first-line drugs. The use of ethionamide has been limited because of its low therapeutic index. Ethionamide causes severe side effects, even at the lowest doses required for its mycobactericidal activity. Wolff and Nguyen review recent efforts to boost the activity of ethionamide against M. tuberculosis [5]. Two research groups recently reported the identification of ethionamide potentiators that significantly sensitize M. tuberculosis to the drug through inactivation of a key resistance mechanism [6,7]. It is hoped that the introduction of effective potentiators would allow ethionamide to be used as a first-line anti-tuberculous agent. Besides β-lactams and ethionamide, an even older group of antibiotics, antifolates, were recently shown to be effective in TB treatment. Antifolates were the first antimicrobial agents used for effective cure of bacterial infections, but they have been largely abandoned and ignored for TB trials. However, recent studies showed that sulfonamides such as sulfamethoxazole are potent against M. tuberculosis [8–10]. As seen before with dapsone [11], repurposing of these classical agents could provide quick relief to the current epidemic of drug-resistant TB. A pressing issue that prevents more widespread use of antifolates is the lack of effective potentiators. Successful targeting of antifolate resistance thus plays a key role in the possible expansion of antifolate use in TB therapies [5].

M. tuberculosis is notorious for its ability to circumvent the antibacterial activity of antibiotics. The waxy, impermeable cell wall of M. tuberculosis presents a serious challenge to anti-tuberculous drug development, preventing penetration of both hydrophilic and hydrophobic compounds. The reduction of bioavailability of agents due to this cell wall barrier undermines the therapeutic index of existing antibiotics and makes the search for new drugs a difficult task. The review by Favrot and Ronning discusses recent efforts to develop chemicals that destabilize the mycobacterial cell wall [12]. This approach would allow sensitization of M. tuberculosis to many available, clinically approved drugs. Accumulating evidence also supports an important role for efflux pumps, which are mounted on the mycobacterial cell wall, in the intrinsic drug resistance of M. tuberculosis [13]. Chemicals that manage to travel through the tough cell wall could be quickly expelled from the cytoplasm by these molecular pumps. Viveiros et al. provide a comprehensive review on the role of efflux pumps in drug resistance of M. tuberculosis [14]. These authors also discuss the potential of available inhibitors in blocking the activity of these pumps, thereby further potentiating the antimycobacterial activity of available drugs.

Besides the impermeable cell wall and efflux pumps, specialized drug resistance mechanisms operating within the M. tuberculosis cytoplasm provide intrinsic drug resistance. Many of these systems are co-regulated and inducible in the presence of antibiotics, thanks to global regulators that are responsive to antibiotics. The evolution of these regulatory proteins toward antibiotic responses might play a key role in specializing the function of structural drug resistance proteins that might have existed long before antibiotics were introduced into clinical practice [15]. There are at least two such antibiotic-responsive global regulators thus far identified in M. tuberculosis. lsr2 and whiB7 genes have been reported to regulate the transcription of multiple structural genes involved in intrinsic antibiotic resistance in mycobacteria. In this issue, Liu and Gordon provide their insights into the functions of lsr2 [16], while Burian et al. discuss the biology of whiB7 [17]. Although much remains to be done to assess their suitability as drug targets, the prospect that a single compound inhibiting one of these systems could sensitize M. tuberculosis to multiple antibiotics simultaneously makes Lsr2 and WhiB7 attractive targets for anti-tuberculous drug development.

A key factor that contributes to the prevalence of M. tuberculosis is its ability to persist within infected hosts, during which M. tuberculosis circumvents both the innate and adaptive immune systems. Targeting virulence factors or host mechanisms involved in pathogenesis might help render M. tuberculosis more vulnerable to other drugs that inhibit the bacillus itself. The review article written by Jayachandran et al. discusses these possibilities [18]. These experts emphasize the paramount importance of signaling pathways from both the host and M. tuberculosis as feasible targets for such medicinal interventions.

Host persistence and antibiotic tolerance of pathogenic bacteria might be related to the ability to form community-like structures within biofilms. Whether or not biofilm growth constitutes an important factor in the pathogenesis of M. tuberculosis remains to be established. Nevertheless, targeting M. tuberculosis persistence is an attractive idea, as successful interventions would sensitize the bacillus, not only to the host defense mechanisms, but also to chemotherapeutic agents. Islam et al. provide their perspectives on the application of in vitro biofilm to studies of M. tuberculosis persistence against antibiotics [19]. If these hold true, research using this system would allow breakthroughs in our understanding of M. tuberculosis drug tolerance during TB latency.

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