A new Mycobacterium leprae dihydropteroate synthase variant (V39I) from Papua, Indonesia

Abstract

Indonesia had the third highest number of new leprosy cases worldwide in 2017. This disease is still prevalent in Papua province, where the number of new cases in 2014 (3.0 cases per 10,000 people) is considered highly endemic and is well above the World Health Organization's (WHO) cutoff of <1 new case per 10,000 people. Since 1995, the WHO has supplied Papua province with a multi-drug therapy (MDT) in which multibacillary (MB) patients are treated with rifampicin, clofazimine, and dapsone and paucibacillary (PB) patients are treated with rifampicin and dapsone. Recent published data on global drug resistance reported cases of dapsone resistance in relapsed and newly diagnosed cases in Indonesia during this period. The detection of specific point mutations in folP1 that encode dihydropteroate synthases (DHPS) is used exclusively to identify dapsone resistant strains of Mycobacterium leprae . The purpose of this study was to test for the presence of folP1 mutations in M. leprae strains isolated from patients residing in Papua Island, Indonesia who responded less effectively to dapsone. This study identified a folP1 point mutation that changed a valine (V) residue at amino acid position 39 (from the N-terminus) to isoleucine (I) (V39I) of DHPS. The V39I variant is located within an α-helix motif that may not much affect its structure. Molecular docking analysis indicated that the binding affinity of the V39I variant was slightly reduced as compared to the wildtype of DHPS. The decreasing of affinity may have a consequence of increasing inhibition constants (Ki) of dapsone on the variant V39I of DHPS. The data suggest that the DHPS V39I variant might cause less sensitive to dapsone. However, in vivo studies (e.g., mouse footpad model) are needed to confirm the effect of this DHPS variant on dapsone therapy.

A Review on Agents for the Treatment of Leprosy Infection

“…To tackle, this the research is ongoing to inhibit the enzyme ribonucleotide reductase (RNR) because of its involvement in the biosynthesis of nucleotides [49,[75][76][77][78]. Many reports also suggested that the enzyme dihydropteroate synthase (DHPS) is also one of the important enzymatic targets [79,80]. Hence, we thought to include the details of the agent developed for inhibiting the RNR and DHPS action.…”

The genetic determinants of <i>Mycobacterium leprae</i> resistance to antimicrobial drugs

“…Моментом начала химиотерапии лепры, несмотря на низкую эффективность лечения и многочисленные нежелательные эффекты для пациента, можно считать применение сульфонов [20]. Монотерапию лепры бактериостатическим препаратом дапсон (4, 4'-диаминодифенилсульфон) проводили с момента его открытия в 1935 г. Известно, что мишенью дапсона является дигидроптероатсинтаза, ключевой фермент в биосинтезе фолиевой кислоты у бактерий, включая M. leprae [21,22]. Особенностью метаболизма микобактерий является эндогенный синтез фолиевой кислоты, в то время как организм человека может усваивать фолиевую кислоту, поступающую извне.…”

“…Самая распространенная мутация -это С/T транзиция (CCC→CTC) в 55 положении кодона, приводящее к замене лейцин→пролин (Leu→Pro), которая снижает эффективность терапии дапсоном [33] (таблица). Также обнаружена замена Val→Ile в 39 аминокислотной позиции дигидроптероатсинтазы, возникающая в результате трансверсии Т/А (GTC→GAC) [22].…”

Discovery of sulfone-resistant dihydropteroate synthase (DHPS) as a target enzyme for kaempferol, a natural flavanoid

“…There are three DHPS catalytic active sites, pterin, pABA and anion-binding pocket, of which sulfa drugs mostly target pABA active site pocket (Achari et al, 1997;Babaoglu et al, 2004;Roland et al, 1979;Woods, 1940;Zhu and Stiller, 2001). The point mutations (at position 53 and 55) leading to drug resistance in M. Leprae are located near the pABA active site particularly at the flexible and conserved loops, which might influence the binding environment of the active site (Maladan et al, 2019;Matsuoka et al, 2007;Nakata et al, 2011). Moreover, the lack of availability of the crystal structure of M.leprae DHPS hampered the efforts to understand the structural basis of sulfa drug resistance and to discover novel inhibitors.…”