An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety

Antillón, Armando; Vries, Alexander H. de; Espinosa-Caballero, Marcel; Falcón-González, José Marcos; Romero, David F.; González–Damián, Javier; Jiménez-Montejo, Fabiola Eloísa; León-Buitimea, Ángel; López-Ortíz, Manuel; Magaña, Ricardo; Marrink, Siewert J.; Morales‐Nava, Rosmarbel; Periole, Xavier; Reyes‐Esparza, Jorge; Rodríguez-Lozada, Josué; Santiago-Angelino, Tania Minerva; González, M. Cristina Vargas; Regla, Ignacio; Carrillo‐Tripp, Mauricio; Fernández‐Zertuche, Mario; Rodríguez‐Fragoso, Lourdes; Ortega‐Blake, Iván

doi:10.1371/journal.pone.0162171

Cited by 33 publications

(51 citation statements)

References 63 publications

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“…Preliminary in vitro and in vivo studies have shown that the amphotericin A21 derivative has fewer nephrotoxic and haemolytic effects than the original molecule. Additionally, its lethal dose 50 (LD 50 ) in mice was almost seven times higher when compared to AmB 14 . This derivative is a promising candidate for use in the treatment of invasive fungal infections, even though additional studies are still required to demonstrate its safety.…”

Section: Introductionmentioning

confidence: 99%

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Ortega‐Blake

Fernández‐Zertuche

Regla

et al. 2021

Basic Clin Pharma Tox

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Safety studies are essential in drug development. This study evaluates the safety of Amphotericin A21 (AmB‐A21), a derivative of amphotericin B with antifungal therapeutic potential. We performed a chronic toxicity study, a targeted organ study and a dermal irritation test. To evaluate chronic toxicity, 18 male adult rats were treated orally with AmB‐21 (2 mg/kg) for 26 weeks. The effects on body‐weight and animal health were measured, and haematological, clinical chemistry and histopathological tests were conducted on various organs. In the target organ toxicity study, male adult rats received a daily oral dose of AmB‐21 (2 mg/kg) for 6 and 17 weeks; testicle histology and testosterone levels were then evaluated. For the dermal irritation study, AmB‐21 (200 and 1000 mg/kg) was placed on the skin of adult male rabbits; macroscopic and microscopic studies, as well as haematological and clinical chemistry tests were then conducted. The chronic toxicity study revealed that AmB‐21 caused testicle damage, and the testicle‐targeted study showed structural alterations and changes in testosterone levels at 17 weeks. However, these alterations were no longer observed 8 weeks after discontinuation of treatment, and the testes showed very similar characteristics to those in the control group. The dermal irritation study showed skin thickening and reddening in rabbits treated with 2000 mg of AmB‐A21 after 14 days of exposure. This same group also showed changes in liver enzymes, renal parameters and platelet levels. Based on our results, we consider AmB‐21 to be a potential candidate for safe, long‐term antifungal treatment given its reduced side effects.

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Section: Introductionmentioning

confidence: 99%

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Ortega‐Blake

Fernández‐Zertuche

Regla

et al. 2021

Basic Clin Pharma Tox

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“…In addition, it is also used for the treatment of visceral leishmaniasis (VL) caused by protozoan parasites of the genus Leishmania ( Chattopadhyay and Jafurulla, 2011 ). Unfortunately, treatment of these, often fatal, systemic infections usually requires high dosages of amphotericin B, resulting in adverse side reactions in the human body such as nephrotoxicity, shaking chills, fever and anemia ( Gallis et al, 1990 ; Zotchev, 2003 ; Antillón et al, 2016 ). Consequently, new amphotericin-like polyenes with less severe side effects for humans and stronger antimycotic and antiparasitic activities are highly sought after as alternatives to the conventional treatments ( Tevyashova et al, 2013 ; Antillón et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

et al. 2020

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The rise of drug-resistant fungal pathogens urges for the development of new tools for the discovery of novel antifungal compounds. Polyene antibiotics are potent agents against fungal infections in humans and animals. They inhibit the growth of fungal cells by binding to sterols in the cytoplasmic membrane that subsequently causes pore formation and eventually results in cell death. Many polyenes are produced by Streptomycetes and released into the soil environment, where they can then target fungal hyphae. While not antibacterial, these compounds could nevertheless be also perceived by bacteria sharing the same habitat and serve as signaling molecules. We therefore addressed the question of how polyenes such as amphotericin B are perceived by the soil bacterium, Bacillus subtilis. Global transcriptional profiling identified a very narrow and specific response, primarily resulting in strong upregulation of the lnrLMN operon, encoding an ABC transporter previously associated with linearmycin resistance. Its strong and specific induction prompted a detailed analysis of the lnrL promoter element and its regulation. We demonstrate that the amphotericin response strictly depends on the two-component system LnrJK and that the target of LnrKdependent gene regulation, the lnrLMN operon, negatively affects LnrJK-dependent signal transduction. Based on this knowledge, we developed a novel whole-cell biosensor, based on a P lnrL-lux fusion reporter construct in a lnrLMN deletion mutant background. This highly sensitive and dynamic biosensor is ready to be applied for the discovery or characterization of novel amphotericin-like polyenes, hopefully helping to increase the repertoire of antimycotic and antiparasitic polyenes available to treat human and animal infections.

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“…mammalian cells, polyene macrolides are the most toxic clinically used drugs, which substantially limits their pharmacological application [ 11 , 12 ]. Many attempts have been made to produce polyene derivatives and conjugates with reduced side effects [ 13 – 20 ]. Recently, benzoxaboroles, which are privileged structures in medicinal chemistry due to their desirable physicochemical and drug-like properties [ 21 ], were used for the synthesis of AmB-benzoxaborole hybrid antibiotics [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Pore-forming activity of new conjugate antibiotics based on amphotericin B

et al. 2017

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A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes—causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles—and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.

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An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety

Cited by 33 publications

References 63 publications

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Preclinical safety evaluation of amphotericin A21: A novel antifungal

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

Pore-forming activity of new conjugate antibiotics based on amphotericin B

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