Introduction

Although the implementation of long-term dapsone therapy made the effective treatment of leprosy possible [1], within a few decades resistance to this antibiotic was observed among patients undergoing treatment [2]. This resistance resulted in high rates of relapse, primarily due to inappropriate monotherapy (secondary resistance). As a consequence, dapsone-resistant leprosy was transmitted to susceptible persons, resulting in new cases of dapsone-resistant leprosy (primary resistance) [3]. New drugs were subsequently identified as effective anti-leprosy drugs; however, acquired resistance to these drugs was also observed when they were used as a monotherapy [4], [5]. Consequently, a strategy developed for the treatment of tuberculosis [6] was implemented, in which multiple effective antibiotics were combined to prevent the selection of antibiotic-resistant strains. The multi-drug therapy (MDT) recommended in 1982 by the World Health Organization (WHO) as the standard treatment for leprosy is a combination of dapsone, rifampin, and clofazimine [7]. MDT has been effective at reducing both the prevalence and the incidence of leprosy (see Chapter 1.1; Chapter 1.2) at a global level [8], [9]. However, drug resistance is still observed [10]. Approximately 211,973 new cases of leprosy were reported in 2015, demonstrating that the battle against leprosy continues and that research in chemotherapy must continue [11].

In this review, we describe the antibacterial activity of the antibiotics used to treat leprosy and, if known, their mechanisms of resistance in M. leprae. We also describe the methods used to study antibiotic activity, drug susceptibility, and resistance, and report on the efforts to monitor global drug resistance in leprosy [12].

Mode of Action and Antibacterial Activity

This discussion begins with the anti-leprosy drugs included in the standard WHO-recommended MDT treatment of leprosy: dapsone, rifampin, and clofazimine. Next, a number of newer antimicrobial agents that possess various degrees of bactericidal activity against M. leprae, such as the fluoroquinolones, the macrolides, and the tetracyclines, are discussed. These drugs have been described as effective in experimental infections in mice and in human clinical trials. The modes of action for most of the effective classes of drugs against M. leprae occur at the level of nucleic acid and protein synthesis. However, for many anti-leprosy drugs, the actual mechanisms of action are not known but inferred from studies of M. tuberculosis.

Dapsone

The first effective treatment for leprosy was promin, a sodium glucosulfone (diamino-azobenzene 4’-sulfonamide) introduced in 1943 [13]. Six years later, a more effective oral sulfone, dapsone (4,4’-diaminodiphenylsulfone) (Figure 1A), replaced promin and is still a fundamental component of MDT for leprosy. Sulfone drugs target the dihydropteroate synthase (DHPS), a key enzyme in the folate biosynthesis pathway in bacteria (Figure 2), by acting as a competitive inhibitor of p-aminobenzoic acid (PABA) [14], [15]. The inability to synthesize folate leads to a depletion of adenosine, guanosine, and thymidine pools. The effect of dapsone on folate biosynthesis has been confirmed in M. leprae [16], [17].

FIG 1 Biochemical Structures of Anti-Leprosy Drugs.

FIG 2 Inhibition of Folic Acid Biosynthesis by Dapsone.

Dapsone is a competitive inhibitor of para-amino benzoic acid (PABA), a critical substrate for folate biosynthesis. Dapsone blocks the condensation of PABA and 7,8-dyhydro-6-hydroxymethylpterin-pyrophosphate from forming 7,8-dihydrofolic acid. The key enzyme in this step is the dihydropteroate synthase (DHPS) encoded by the folP gene. Dapsone competitively inhibits this condensation and ultimately results in the decreased production of tetrahydrofolate, an essential component of nucleic acid biosynthesis in M. leprae.

Dapsone Resistance

Recognizing that dihydropteroate synthase (DHPS) is the target of sulfonamides and derivatives, including dapsone [68], studies designed to characterize the mechanism of dapsone resistance in M. leprae have relied upon direct sequencing of the two genes encoding DHPS1 and DHPS2 (folP1 and folP2, respectively) from dapsone-susceptible and -resistant M. leprae isolates. Missense mutations were found within codons 53 and 55 of folP1 (Figure 5) in dapsone-resistant mutants [17], [69]. Because no mutations were identified in the DHPS2 genes from the resistant mutant, folP2 was ruled out as a functional part of dapsone resistance [70]. Mutations identified in the dapsone-resistant mutant resulted in a DHPS1 enzyme with decreased dapsone binding [17]. Since the same mutations were repeatedly observed in codons 53 and 55 of the folP1 gene in characterized dapsone-resistant strains, this region was designated the “drug resistance-determining region” (DRDR) for dapsone resistance [71] (Table 1). A search for folP1 mutations in M. leprae isolates demonstrated that all M. leprae strains with high-level dapsone resistance (multiplication in mice fed with 0.01% dapsone), and the majority of M. leprae strains with moderate-level dapsone resistance (multiplication in mice fed with 0.001% dapsone) contained missense mutations within codons 53 and 55 [69], [71], [72]. One isolate with low-level resistance (multiplication in mice fed with 0.0001% dapsone but no higher concentrations) also contained a mutation in codon 55 [71].

References

1. ^{^}LoweJ. 1950. Treatment of leprosy with diamino-diphenyl sulphone by mouth. Lancet 1:145–150.
2. ^{a, b}PearsonJ,ReesR,WatersM. 1975. Sulfone resistance in leprosy. A review of 100 proven clinical cases. Lancet 2:69–72.
3. ^{^}PearsonJM,HaileGS,ReesRJ. 1977. Primary dapsone-resistant leprosy. Lepr Rev 48:129–132.
4. ^{^}JacobsonRR,HastingsRC. 1976. Rifampin-resistant leprosy. Lancet 2:1304–1305.
5. ^{a, b, c, d}CambauE,PeraniE,GuilleminI,JametP,JiB. 1997. Multidrug-resistance to dapsone, rifampicin, and ofloxacin in Mycobacterium leprae. Lancet 349:103–104.
6. ^{^}CohnML,MiddlebrookG,RussellWF,Jr. 1959. Combined drug treatment of tuberculosis. I. Prevention of emergence of mutant populations of tubercle bacilli resistant to both streptomycin and isoniazid in vitro. J Clin Invest 38:1349–1355.
7. ^{a, b, c}WHO. 1982. Chemotherapy of leprosy for control programmes. World Health Organization, Geneva.
8. ^{a, b}JiBH. 1985. Drug resistance in leprosy—a review. Lepr Rev 56:265–278.
9. ^{^}WHO. 2013. Global leprosy: update on the 2012 situation. Weekly Epidem Record 88:365–380.
10. ^{a, b}WHO. 2011. Surveillance of drug resistance in leprosy. Weekly Epidem Record 23:233–240.