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Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 121
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122 Organic Compounds to Combat Neglected Tropical Diseases, 2014, 122-14 8
CHAPTER 4
LEPROSY
Chasing Potential Antileprotic Compounds
Dênis Pires de Lima
1,*
and Davidson Pires de Lima
2
1
Federal University of Mato Grosso do Sul , Institute of Chemistry, 79070-900,
Campo Grande, MS, Brazil and
2
Federal University of Minas Gerais,
Department of Clinical Medicine/Faculty of Me dicine, 30130-100, Belo
Horizonte, MG, Brazil
-Mother, could you hold me in your lap?
-I am sorry, I should not my son. I am suffering from contagious
disease.
-What kind of disease, mother?
-The one whose name nobody mentions. It is better you don’t know.
Abstract: Leprosy is still considered one of the world’s important chronic diseases.
Although multidrug therapy (MDT) has contributed to decline of its incidence, there are
still hundreds of thousands of new cases each year. A full understanding of the
physiological, clinical, transmission, immunology, genetic and bacterial aspects of this
disease is very important to track the problem by multidisciplinary scientific
investigation. Excellent work on the design and synthesis of new drugs to treat Leprosy
is being performed all over the world, and is included in this manuscript. Nevertheless,
studies to find more effective drugs to treat leprosy are still needed. Leprosy and others
parasitic, bacterial, viral and protozoan infections form the group of neglected tropical
diseases (NTD) and are among the leading causes of chronic disability and poverty in
low- and middle-income countries.
Keywords: Antileprotic, leprosy, synthetic studies.
1. THE DISEASE
The above sad and depressing dialog was witnessed by these authors occurring in
a family that faced leprosy in one of its members. The stigma associated with the
disease is deeply impressed into our society’s psyche. Leprosy or Hansen's
*Address correspondence to Dênis Pires de Lima:
Federal University of Mato Grosso do Sul, Institute of
Chemistry, 79070-900, Campo Grande, MS, Brazil; Tel/Fax: +55 67 3345 3676; E-mail: denis.lima@ufms.br
Send Orders for Reprints to reprints@benthamscience.net
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 123
disease is a chronic clustered familial and geographical disease [1] - caused by a
unique germ species – Mycobacterium leprae (M. Leprae). Nevertheless, an
ancient deforming disease dating back to 600 BC is still insufficiently understood
and often feared by public and even by some in the health care activities [2, 3]. It
is a serious disease with neural damage bringing about consequent disabilities,
and dermatologic lesions leading to unsightly appearance, both causing
resentment for the patient and strengthening the overwhelming prejudices leading
to the stigma of leprosy for humans. Leprosy can also be a fatal disease, in acute
and chronic painful instances [4].
Fortunately, the perspective for patients has noticeably improved over the last
three decades with the introduction of multidrug therapy (MDT), and management
strategies that have somewhat lessened the stigma of this diagnosis. Because of
MDT, more than 14 million leprosy patients had been cured over the last 20 years,
and its prevalence rate has dropped from 21.1 cases per 10,000 population in 1985
to almost 1 per 10,000 at 2001 in some countries [5]. Although the prevalence of
Hansen’s disease in the world has been reduced significantly, leprosy is still a
major health problem in Asia, Latin America, and Africa, and along with 12
others disabling conditions form the group of neglected tropical diseases (NTD)
leading to poverty, limitation and suffering [6]. At the beginning of 2009, the
registered prevalence of the disease globally was 213,036 cases; the number of
new cases detected during 2008 was 249,007, a 4% decrease (9126 cases)
compared with the previous year [7].
In 1991, the World Health Assembly adopted a resolution to eliminate leprosy by
2000, defining elimination as reducing the prevalence to below one case per
10,000 population. By 2005, the goal had not been met, despite the provision of
free multidrug therapy from 2000 onwards. The occurrence of the disease
contrasts clearly, with the overwhelming majority of cases being found in
developing countries. In 2000 about 90 percent of cases were reported in just 11
countries, led by India and Brazil [5]. However, with ever-increasing international
travel, cases of leprosy may be present anywhere.
Although the prevalence of leprosy has declined in the last decades, the disease is
not going to disappear any time soon, and the global initiative to eliminate leprosy
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124 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
by lowering its incidence to <1/10,000 has not reached countries like India,
Brazil, Indonesia, Nepal, and Nigeria, the five most endemic countries [7]. The
combined prevalence rate in these countries is about 4 by 10,000. However, this
registered prevalence is far from the real number of undiagnosed, hidden,
treatment neglected and unrecorded cases [8]. Mathematic models from scenario
analysis investigating the impact of current strategies for the elimination of
leprosy advise about the risks of relaxation of control after year 2005 [9].
To coincide with World Leprosy Day on January 25, 2009 the Lancet Infectious
Diseases journal published a future issue by Kathryn Senior highlighting the silent
stigma that surrounds the victims of this ancient disease [10, 11]. It is stated
therein that “although WHO (World Health Organization) have gone a long way
to eliminating leprosy as a public-health problem, there may be barriers to
achieving and sustaining elimination in countries that still have a high burden of
disease”.
1.1. The Bacteria
M. leprae has a very exciting microbiological history. Since its discovery by
Gerhard Henrik Armauer Hansen in 1873 as the first human disease caused by a
germ, preceding that of tubercle bacillus by nine years, it remains as the only
bacterium causing human disease that has not been cultured in vitro.
Consequently, knowledge of its biological properties, including its sensitivity and
resistance to drugs, comes from bacteria isolated from the nine bands armadillos
[12] or inoculation into the footpads of immunosuppresed or normal mice [13].
1.1.1. Morphology
M. leprae are gram positive and acid fast mycobacteria with an irregular or
granular appearance. A modification of this acid fast stain is known as the Fite
stain and has a weaker acid for supposedly more delicate M. leprae bacilli. It is a
straight or slightly curved rod bacillus, 1-8 μm long and 0.3μm in diameter. In
lepromatous leprosy patients, the most vulnerable in their immunologic status,
bacilli arrange in clumps, termed globi, with more than 1000/bacilli per high field
power (HFP) on microscope. In immunologically more resistant tuberculoid
patients, the presence of bacilli is rare, or entirely absent. As will be seen in the
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 125
clinical and immunological classification, between these two extremes or polar
forms are intermediate subtypes of patients presenting with a variable numbers of
bacilli per HFP in their lesions [14-16].
1.1.2. Biological Properties
Since M. leprae cannot be cultured in vitro, our knowledge about its biology and
several aspects of the disease are discovered trough infected armadillos and
footpad inoculation in immunosuppresed mice. Based in this methodology the
doubling time of M. leprae has been estimated to be 11 to 13 days, a peculiar slow
rate of multiplication, considering for instance 20 hours of generation time for
M. tuberculosis [16]. Footpad techniques in normal immunocompetent mice have
also been used to access potency, minimal effective dose (MED), minimal
inhibitory concentration (MIC), antibacterial properties, and detection of drug
resistance of antileprosy drugs [14, 17, 18].
The cell wall contains an array of peptidoglycans linked to the chemical hallmark
of mycobacteria genera, the mycolic acids. The immunological specificity of
M. leprae is given by a phenolic glycolipid (PGL-1), the dominant lipid in its cell
wall [19], and absent from M. tuberculosis. PGL-1 is a target for recent studies in
disease diagnosis and pathogenesis [20, 21].
1.1.3. Genomic
There is no apparent variation in strains of M. leprae, thus the same bacteria
causes the disease in every part of the world. However, a “variant” not related to
the type of leprosy has been identified [16], and investigations to discover genetic
markers to reveal genotypic variation have met with limited success [14, 22, 23].
Although not yet cultured in vitro; M. leprae was opened by genoma sequence at
the beginning of last century [24]. M. leprae has undergone an extreme case of
reductive evolution when compared with its close relative M. tuberculosis.
Comparison between both mycobacteria reveals a real genomic scarcity of
M. leprae, smaller than M. tuberculosis (3.3 Mb for M. leprae versus 4.4 Mb for
M. tuberculosis) and with major reduction in G-C content. Besides, M. leprae
contains 1,113 pseudogenes, lost through its evolution. Not surprisingly,
M. leprae had suppressed several metabolic pathways compelling to a
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126 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
bacteriologic status of very specific growth requirements, which may contribute to
its narrow ecological niche [14, 15, 24]. These speculations through M. leprae’s
genome has thus provided insight into why the leprosy bacillus is an obligate
intracellular parasite and has provided the basis for future experimentation to
better understand its pathogenicity.
1.2. Transmission, Immunology and Classifications
Leprosy is a polymorphic disease with distinct manifestations between individuals
living in same families and ecological niches, and in the same person during life.
The human being is the only reservoir of the infection, and the transmission is
made by contact into families or human groups [25]. Cutaneous lesions, other
natural secretions such as maternal milk, sweat, feces, urine, sperm and
respiratory tract are proposed to be the route of infection, but the exact mechanism
of transmission is not known [14, 16].
The incubation period is controversial because of problems in identification of
reference points in the natural history of the disease. There are reports of
incubation periods as short as a few weeks and longer than 30 years, but the
incubation period is generally prolonged falling between 2 to 5 years [16, 26, 27].
Being an infectious disease caused by a unique agent, the clinical and pathological
presentation depends almost exclusively upon host biology. Until now there is no
indication of an environmental role or from route of transmission for the protean
manifestations of the disease.
1.3. Natural Immunity and Immunology
In spite of its great infectivity, most people who are infected with M. leprae
recover naturally without ever having symptoms of disease and few people
develop leprosy. In the past, the difference of this behavior has promoted the base
of prejudice determined by the conception of a persuasive sign of a “natural sin”
among members of a family. Nowadays, there is strong epidemiological evidence
that genetic factors influence susceptibility both to leprosy (leprosy “per se”)
regardless the subtype, and to leprosy type. The role of major histocompatibility
complex (MHC1) polymorphisms in this determination has been found in several
linkages and association studies albeit not very powerful [28].
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 127
Associations for susceptibility to leprosy with the frequency of Human Leukocyte
Antigen (HLA) types have been proposed in connection with HLA-DR2 in
distinct chromosome regions [15]. Recently other genes have been identified
carrying loci associated with overall susceptibility of human population to
M. Leprae [29]. Variants of genes that regulate immune response are associated
with susceptibility to infection with M. Leprae [30].
If natural immunity is not capable of coping with the infection, the immunologic
host response is called upon to play the most and critical role. Protective
immunity in leprosy was associated with lymphocyte expression of interleukin-2
and interferon-γ whereas susceptibility with presence of IL-4, IL-5 and IL-10 and
not γ-interferon [31]. Multibacillary infections is thought to be associated with
type 2 helper (Th2) cell response and paucibacillary infection with an immune
response mediated by type 1 helper (Th1) cells [32].
1.4. Classifications
Leprosy is a peripheral neuropathy disease initiated by a direct infection of
M. leprae to Schwann nerve cells, surrounded by an assembly of inflammatory
events [14]. The course of this primary lesion often extends many years beyond
the cure of the infection and may have severe consequences. In general, skin
lesions are accompanied by neuropathy and the sum of both turn out to be the
clinical picture of the disease. In patients with early or mild disease nerve damage
may not be evident except by histopathological examination of nerves. It is
fundamental to recognize that all the clinical presentation of leprosy is secondary
to the capacity of cellular immune response of each infected person. The balance
between cellular phenomena and systemic events that compose this set of
immunity provide the manifestation of disease and its subtype.
The best acceptable system of classification of leprosy was proposed by Ridley
and Jopling through analysis of cases in their initial presentation and their
evolution post dapsone treatment [33]. This classification is based in a
combination of clinical manifestations, the bacillary load and histopathology, and
can establish five strictly defined groups in a spectrum of patient’s resistance to
infection. The system classifies patients into tuberculoid (TT), borderline
tuberculoid (BT), midborderline or simple borderline (BB), borderline
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128 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
lepromatous (BL) and lepromatous (LL). By this classification the subtypes
tuberculoid (TT) and lepromatous (LL) represent the poles of disease. So TT type
discloses a marked immunologic patient’s resistance to infection, with very few
bacilli in lesions. On the opposite pole, LL is a nonresistant, highly infected form
of disease. They are called stable, so their disease manifestation does not change
over time. Between both are subtypes (BT, BB, and BL) with a behavior variable
with time and treatment. These subtypes can migrate in directions of tuberculoid,
more resistant, or lepromatous, nonresistant.
Apart from this classification is a distinct form named indeterminate, presumed to
be an early manifestation of the disease. Patients with indeterminate form are
young children, with hypopigmented skin lesions of short duration and lack of
neurologic involvement or very slight symptoms, and can resolve spontaneously.
World Health Organization (WHO) established a much more simplified
classification system considering circumstances where diagnosis, treatment and
follow up of patients are made or must be done [34]. At first, based on the
presence of bacilli in skin slit smears (SSS), the proposed classification was a
division of two types only: paucibacilar (negative SSS) and multibacilar (positive
SSS). Because services for processing SSS are not always available, patients
could be classified in clinical grounds only, an essentially operational
classification to serve as a basis for chemotherapy. The proposed classification is:
Paucibacillary single-lesion leprosy (one skin lesion).
Paucibacillary leprosy (2 – 5 lesions).
Multibacillary leprosy (more than 5 lesions).
1.4.1. Resistance to Leprosy: The Lepromin Test
A test which could provide a measure of individual pattern of response to
M. leprae is the lepromin test produced by intradermal injection of a mixture of
these bacterial antigens and evaluated 4 weeks later. The most frequent used
antigen preparation is the Mitsuda (also called, lepromin). This test is considered
positive when a palpable induration of 5 mm or more is measured, and identifies
.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 129
individuals capable of mounting a specific cell mediated response to M. leprae
antigens. An induration under 5 mm is suggested to be negative and identifies
those who are not capable to mounting a granulomatous response against
M. leprae antigens.
This is not a diagnostic test for leprosy. It is positive in the forms of TT and BT
leprosy, and negative in LL and BL forms and it may be of value in indicating the
direction of immunological shift in borderline leprosy [4, 14, 35, 36].
1.5. Clinical Presentations
Even though the clinical presentation of leprosy varies significantly, the cardinal
manifestation is a hypopigmented lesion with neurologic signs or symptoms,
including hypoestesia, peripheral nerve thickening or weakness, associated to
autonomic dysfunction such as sweat loss. However, skin lesions could be
erythematous or infiltrative, unique or multiple, almost imperceptible or
deforming, and neuropathy could present with casual sensory changes or serious
neurologic compromise leading to deformities. In addition, the natural evolution
can be flared by reactive reactions, a burst of immunological phenomena, which
modifies acutely the chronic disease character.
Finally, lepromatous leprosy (LL) is a systemic disease, involving multiple
organs. Eye damage is a common and disastrous complication, bones may be
invaded with destruction of facial architecture, leading to collapse of nose, or the
phalanges leading to easy fractures and shortening and distorting the fingers. In
addition, testes, muscles, tendons, and indirectly liver, kidneys and adrenal glands
can be damaged.
If indeterminate form does not cure itself spontaneously the patient enters into the
spectrum of the disease coming up with a clinical appearance modulated by his or
hers cell immunology.
1.5.1. Tuberculoid Leprosy (TT)
This polar type is characterized by single or very few skin lesions with sharp
borders. They are hypopigmented or slight erythematous, with a red or copper
colour, and sometimes the edge is elevated. Lesions are hypoesthetic or definitely
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130 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
anesthetic, with autonomic nerve compromise leading to absence of sweating.
Skin smears result negative for the presence of M. leprae. It has a tendency to
spontaneously healing.
1.5.2. Lepromatous Leprosy (LL)
This nonresistant, highly infected form of the disease is termed polar. It presents
with multiple and widely distributed skin lesions, hypopigmented or
erythematous, with ill-defined margins. They are symmetrically distributed but
spare the more warm body regions of axillae, groins and scalp
[35] Bacilli are
always present in lesions, in great number, often in clumps or globi formation,
accounting for many of the disease characteristics of this pole.
Neurologic symptoms present relatively late, with symmetrical sensory loss
shown by impaired sensation to touch and pin prick or absence of sweating.
Allowed to progress, the disease thickens the skin, leads to loss of eyebrows and
eyelashes, affects lymph nodes, invades nasal mucosa, and destroys hands and
feet. Natural remission does not take place, visceral lesions appear, and eventually
leading to more acute disease and death ensues usually from renal failure and
infections, especially pneumonia [4].
1.5.3. Borderline Leprosy
The borderline forms (BT, BB, and BL) are located inside the spectrum and
present configurations correlated to TT or LL polar forms. They represent the
most frequent clinical and bacteriological forms of the disease and, by definition,
are unstable. That means they could migrate to one or other pole driven by
variation of individual cellular immunity. All show a mixture of the characteristics
of disease at the poles and could have capricious and almost unpredictable
features. BT has features of cellular infiltration associated with bacterial growth,
in BL bacterial growth is predominant but cellular reaction is still evident. BB in
the centre of the spectrum represents the “instability peak” [4, 33, 35].
1.6. Reactions
Two distinct types of reactions can occur in leprosy patients before, during or
following the achievement of treatment. Type 1, or reversal reactions, are clinically
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