Development of Novel Aminoglycoside (NB54) with Reduced Toxicity and Enhanced Suppression of Disease-Causing Premature Stop Mutations

Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania , affects millions of people worldwide. Aminoglycosides are mostly known as highly potent, broad-spectrum antibiotics that exert their antibacterial activity by selectively targeting the decoding A site of the bacterial ribosome, leading to aberrant protein synthesis. Recently, some aminoglycosides have been clinically approved and are currently used worldwide for the treatment of leishmaniasis; however the molecular details by which aminoglycosides induce their deleterious effect on Leishmaina is still rather obscure. Based on high conservation of the decoding site among all kingdoms, it is assumed that the putative binding site of these agents in Leishmania is the ribosomal A site. However, although recent X-ray crystal structures of the bacterial ribosome in complex with aminoglycosides shed light on the mechanism of aminoglycosides action as antibiotics, no such data are presently available regarding their binding site in Leishmania . We present crystal structures of two different aminoglycoside molecules bound to a model of the Leishmania ribosomal A site: Geneticin (G418), a potent aminoglycoside for the treatment of leishmaniasis at a 2.65-Å resolution, and Apramycin, shown to be a strong binder to the leishmanial ribosome lacking an antileishmanial activity at 1.4-Å resolution. The structural data, coupled with in vitro inhibition measurements on two strains of Leishmania , provide insight as to the source of the difference in inhibitory activity of different Aminoglycosides. The combined structural and physiological data sets the ground for rational design of new, and more specific, aminoglycoside derivatives as potential therapeutic agents against leishmaniasis.

show abstract

“…S6. † MIC values in E. coli were previously reported (31)(32)(33). ‡ MIC values were calculated from Matt et al (34).…”

Section: Methodsmentioning

confidence: 99%

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Shalev

Kondo

Kopelyanskiy³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…PTC-124 is an orally bioavailable drug that can be used at significantly lower dosages to obtain higher levels of read-through compared with aminoglycosides [Du et al, 2008]. Newer drugs are also being developed and continued research makes this a potential treatment avenue for nonsense induced diseases [Nudelman et al, 2009]. Clinical trials in Duchene Muscular Dystrophy and cystic fibrosis suggest a promising future for genetic treatment of nonsense mutations including some VHL mutations.…”

Section: Future Prospectsmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

View full text Add to dashboard Cite

Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

show abstract

“…New antibiotics with fewer adverse side effects are in the pipeline (Matt et al 2012;Nudelman et al 2009) and could ultimately reduce the need for otoprotective agents. However, the aminoglycoside antibiotic medications available now are ototoxic, these newer-generation and presumably more costly drugs will be less accessible in developing countries, and thus protective agents are needed.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

Prell

Ojano-Dirain

Rudnick

et al. 2014

JARO

View full text Add to dashboard Cite

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin-induced hair cell death and hearing loss. Here, a combination of nutrients previously shown to reduce oxidative stress in the hair cells and attenuate hearing loss after other insults was evaluated for potential protection against gentamicin-induced ototoxicity. Guinea pigs were maintained on a nutritionally complete standard laboratory animal diet or a diet supplemented with β-carotene, vitamins C and E, and magnesium. Three diets with iterative increases in nutrient levels were screened; the final diet selected for study use was one that produced statistically reliable increases in plasma levels of vitamins C and E and magnesium. In two separate studies, significant decreases in gentamicin-induced hearing loss at frequencies including 12 kHz and below were observed, with less benefit at the higher frequencies. Consistent with the functional protection, robust protection of both the inner and outer hair cell populations was observed, with protection largely in the upper half of the cochlea. Protection was independently assessed in two different laboratories, using two different strains of guinea pigs. Additional in vitro tests did not reveal any decrease in antimicrobial activity with nutrient additives. Currently, there are no FDA-approved treatments for the prevention of gentamicin-induced ototoxicity. The current data provide a rationale for continued investigations regarding translation to human patients.

show abstract

Development of Novel Aminoglycoside (NB54) with Reduced Toxicity and Enhanced Suppression of Disease-Causing Premature Stop Mutations

Cited by 168 publications

References 43 publications

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Genetic analysis of von Hippel-Lindau disease

Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

Contact Info

Product

Resources

About