Drug resistance in Leishmania parasites. Consequences, Molecular Mechanisms, and possible treatments

Abstract

Forward for “Drug Resistance in Leishmania Parasites” Therapeutic unresponsiveness presents a formidable obstacle to the efficient clinical management of many diseases. This is especially true in the case of greatly neglected diseases, such as leishmaniasis, for which the drugs currently in clinical use are limited to few antiquated and toxic compounds. The editor of this volume, Alicia Ponte-Sucre, aptly assembled a group of knowledgeable contributors in the field to cover significant aspects of this serious problem. Readers will find in this volume up-to-date information and a fairly complete coverage of the subject. Chapters are well-arranged in logical order, making it very readable. The significance of individual chapters and their organization in this volume warrant discussion. The introductory chapters in the beginning of this volume provide the necessary background information for those who are unfamiliar with Leishmania and leishmaniasis. The editor begins appropriately with the parasite biology and the complexity of leishmaniasis as a disease of different clinical manifestations, i. e.: [1] innocuous, self-healing cutaneous lesions; [2] the debilitating diffused and mucocutaneous form; and [3] the often fatal visceral disease or kala-azar. How Leishmania has evolved into divergent parasites, which produce such a spectrum disease is a fundamental question of relevance to their inherent phenotype variability, including drug sensitivity. Gabriele Schoenian, Elisa Cupolillo and Isabel Mauricio pointed out correctly in Chapter 1 that clinico-epidemiologically relevant Leishmania need to be collected from all endemic sites to build a comprehensive sequence database for in-depth bioinformatic analyses so that their phylogenetic relationships can be reliably deduced in toto as a foundation to consider their phenotypic differences. Chapter 2 by Lenea Campino and Carla Maia discussed succinctly clinico-epidemiology of canine leishmaniasis with emphasis on their resistance to chemotherapy. With few exceptions, leishmaniasis is indeed epidemiologically a zoonosis. In addition to dogs, the reservoirs include wild canine and rodent species in most places and, additionally, other animals, e. g. sloths, porcupines and armadillos in South America. Where wild animal reservoirs play a role in the transmission of leishmaniasis, its eradication is virtually impossible to consider. The only option then is to control this disease that requires rigorous epidemiological surveillance in the endemic sites so that appropriate measures can be implemented to protect the at-risk population from exposure to the sand fly vectors and to the reservoirs, and to treat those already diseased. The question of vector resistance to pesticides and repellents is of relevance to consider, but this is beyond the scope of this volume. Since neither prophylactic drug nor vaccine is currently available for leishmaniasis, the remaining chapters are mostly concerned with different aspects of drug-resistance in clinical and experimental therapy. Chapter 3 by Jean-Claude Dujardin & Saskia Decuypere addressed the important issue of the regional differences in the epidemiology of drug-resistance versus treatment failure. The latter is clinically of unquestionable importance, but does include a variety of logistic issues beyond the main theme of this volume, ranging from manufacture of anti-leishmanial drugs to their administration and other operational health aspects. The subsequent immunological components are to the point and necessary for their relevance to therapeutic outcome. Chapters 4.1 by Lukasz Kedzierski and Krystal J. Evans briefly reviewed innate/adoptive immunity to Leishmania infection. The authors correctly call attention to the paucity of information on the human immune response to leishmaniasis. Chapters 4.2-4.3 by Katrin Färber and Heidrun Moll, & Bhavana Sethu Lakshmi and Rentala Madhubala introduced specific and general aspects of vaccination strategy and development, respectively. It is prudent to consider these issues in view of the fact that there is only one peptide vaccine, i. e. Leish-111f+MPL-SE, which has been developed to the stage of clinical trials for immunoprophylaxis of leishmaniasis. These chapters on immunology are very pertinent to the main topic of this volume, considering that immune clearance of the infection is almost certainly necessary for a clinical cure of the disease after chemotherapy, since no drug is expected to reach every parasite in any given patient. Chapter 5.1 by Margriet den Boer, Luis Rivas & Jorge Alvar illustrated this point well by alerting readers to the fact that immunosuppression does indeed pose a serious threat to effective therapy of leishmaniasis, as noted from an increase in the incidence of non-healing cases with the spread of HIV-Leishmania co-infection. Immediately followed are chapters that outline the specific problems of the topic in clinical and epidemiological terms. In Chapter 5.2, Shyam Sundar and J. Chakravarty shared their invaluable experience in the clinical managements of Indian kala-azar in Bihar. They call attention to the necessity of identifying markers for screening drug-unresponsive patients and to the consideration of multi-drug therapy to counter the tenacious problems associated with SbV-resistance. Chapter 5.3 by Olga Zerpa & Alicia Ponte-Sucre analyzed the challenges we face for a successful diagnosis, treatment and control of American tegumentary leishmaniasis. The incidence of drug-resistance increases with expansion of the endemic area in this region. This significant problem is compounded by the epidemiological complexity of the disease due to the diversity of etiological agents and reservoir animals. The next five chapters summarize the state of our knowledge on the mechanisms of drug-resistance based on laboratory discoveries. Leishmanial mechanisms of drug-resistance have been elucidated by applying advanced biotechnology. Chapter 6.1 by Patricia Cuervo and Jose Batista de Jesus emphasized the value of high-throughput proteomic analysis of Leishmania and discussed the recent proteomic discoveries of relevance to drug-resistance. Chapters 6.2 and 6.3 by Adriano C. Coelho & Paulo C. Cotrim, and Scott Landfear summarized laboratory discoveries on the functions of Leishmania ABC and non-ABC transporters in drug-resistance, respectively. Point mutations of membrane transporters and/or alterations of their expression levels were mentioned to account for drug-resistance, as noted in other microorganisms. Chapter 6.4 by Mitali Chatterjee reviewed the biochemistry of cellular redox mechanisms in relation to SbV-resistance. The significance of cytosolic SbV-reductase and other enzymes was described, consistent with the well-known mechanism of drug conversion by cellular enzymes to modulate the resistance phenotype. The laboratory discoveries described in the foregoing Chapters represent significant advances in the basic research of drug-resistance, providing molecular targets as its potential biomarkers for evaluation in the clinical samples. The next few Chapters present strategies to develop new drugs and to reverse or alleviate the problem of drug-resistance. Chapter 7.1 by Louis Maes, Raquel Andreia Inocencio da Luz, Paul Cos & Vanessa Yardley bridged the experimental studies on Leishmania in the previous chapters to the next three on drug-development for clinical therapy by considering broadly drug-sensitivity and –resistance in the biological context of host-parasite interactions. In Chapter 7.2, Phillippe Loiseau and Gillian Barratt promoted the rationale approach to the identification of new targets, and screening natural products for effective anti-leishmanials. They also described the strategies of formulation to enhance the effectiveness of drugs in use. Chapter 7.3 by Francisco Gamarro, María P. Sánchez-Cañete & Santiago Castanys focused specifically on the Leishmania mechanisms of resistance to miltefosine via its reduced uptake and efflux, aiming at their characterization for potential use as a clinical marker. Chapter 7.4 by Bruno Pradines discussed the potential and design of flavonoid and other natural ‘chemosensitizers’ to modulate P-glycoproteins as a mechanism to reverse multidrug resistance. The work presented in the foregoing chapters is very pertinent and feasible, calling attention to the necessity of their further development for practical applications. Development of promising laboratory leads into brand-new anti-leishmanials entails a commitment of enormous investments that have been proven too costly to bear by the market force for the unprofitable greatly neglected diseases in general and leishmaniasis in particular. Screening drugs already developed against other diseases for anti-leishmanial activities is more cost-effective, accounting essentially for the only 2 therapeutic additions in clinical use for leishmaniasis. Another strategy is to target host molecules in signaling or other pathways, which are modulated by Leishmania to ensure their successful parasitism. A renewed interest in this approach is spear-headed by the US-NIH by calling for grant applications to develop drugs in that direction. Such anti-host drugs will inevitably have untoward side-effects, but also the potential of their rapid development at a reasonable cost. Therapeutic strategies to counter the development of drug-resistance may include photodynamic therapy, which has been clinically proven and used in treating skin cancer and other diseases. It entails the injection of photosensitizers followed by their excitation with light to rapidly generate a burst of powerful microbicidal ROS. This modality of therapy is unlikely to elicit resistance both in theory and in practice: ROS are known to inactivate multiple targets of cellular molecules with very different properties and the generation of ROS requires a combination of light and photosensitizer, neither of which is cytotoxic in itself. The potential of photodynamic therapy against leishmaniasis has been studied by using, for example, novel endocytic photosensitizers for targeting specificity against the intra-phagolysosomal Leishmania. Photodynamically inactivated Leishmania also have been explored as a potential carrier to deliver vaccines for immuno-prophylaxis and –therapy. The last two chapters discuss practical and theoretical aspects of the issue at hand. Chapter 8.1 by Louis Maes, Paul Cos and Simon Croft pointed out the need to assess drug sensitivity of different Leishmania spp. and to identify molecular markers for resistance under the same conditions by using standardized assays and models. These are very sound proposals, calling for substantial improvements of our ability to duplicate all forms of human Leishmaniasis caused by different Leishmaia spp. in the same in vitro and in vivo models. Chapter 8.3 by Alicia Ponte-Sucre, Emilia Diaz, and Maritza Padrón-Nieves introduced the idea that the development of drug-resistance by Leishmania may change their fitness as a parasite, considering that it is already constantly subjected to stressful conditions throughout their life cycle. This is an intriguing, but complicated question that may be assessed after full elucidation of the mechanisms of Leishmania drug-resistance and pathogenicity so that the actual ‘costs’ for the ‘fitness’ of these respective phenotypes can be estimated. Together, the chapters contained in this volume offer readers not only a comprehensive view of the current status and knowledge of Leishmania drug-resistance but also point out the future direction of the necessary work toward its resolution. By bringing chapters of laboratory research and clinico-epidemiological concerns together into a single volume, the gap between the two becomes evident, high-lighting an urgent need for a closer collaboration between basic scientists and clinicians to foster effective bench-side to bed-side translational research.

Kwang-Poo Chang, Ph.D. Professor of Microbiology/Immunology Chicago Medical School/RFUMS North Chicago, IL 60064, USA Kwangppo.chang@rosalindfranklin.edu