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Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris

Matthew T. Laurie, Corin V. White, Hanna Retallack, Wesley Wu, Matthew S. Moser, Judy Sakanari, Kenny Ang, Christopher Wilson, Michelle R. Arkin, Joseph L. DeRisi

Preprint posted on June 06, 2018 https://www.biorxiv.org/content/early/2018/06/06/331785

Keep your wits about you: Bringing old drugs to the fight against brain-eating amoeba

Selected by Zhang-He Goh

Background of preprint

Infectious disease researchers often worry about the dearth of effective antibiotics around the world. Usually, this concern lies with the rapidly diminishing arsenal of antibiotics following the rise of antimicrobial resistance. But in the case of infections caused by brain-eating amoebae, including Balamuthia mandrillaris, the very issue lies with the lack of any effective antibiotics at all. Despite mankind’s best advances in medicine, mortality rates of brain-eating amoebae remain high at 95%, and no effective treatment exists [1]. The problems standing between the in vitro successes in antibiotic discovery laboratories and the clinical success of these drugs largely cluster around the drugs’ poor pharmacokinetic profiles [1]. The physiological blood-brain barrier often presents a challenge to medicinal chemists and drug formulators in delivering the effective drugs to the brain where the infection resides. To cross this formidable obstacle, extremely high levels of drugs must be administered into the patient’s bloodstream. Such a treatment strategy may ultimately prove intolerable to the patient due to their systemic side effect profiles. Therefore, the lack of effective antibiotics, together with the high mortality rates of these infections, necessitates a stopgap measure. To this end, Laurie et al aim to repurpose drugs in current clinical use that already have favourable pharmacokinetic profiles to treat granulomatous amoebic encephalitis (GAE).

Key findings of preprint

  • From screening a library of clinically-approved compounds in vitro, the authors found that nitroxoline is a favourable candidate for repurposing for targeting mandrillaris infections.
  • A structure-activity-relationship (SAR) study suggests that a metal binding mechanism for the original nitroxoline compound responsible for its antimicrobial activity.
  • Dose-response experiments with various cell lines to represent important physiologic organs (fibroblast, glial cells, kidney, and liver) and both mandrillaris trophozites and cysts revealed that nitroxoline may even be superior to existing drugs used in the standard of care for GAE in two ways. First, nitroxoline was the most effective inhibitor of B. mandrillaris cysts. Second, recrudescence assays showed that nitroxoline eliminates B. mandrillaris populations at 28 µM.

What I like about this preprint

I found the authors’ approach to the problem of medicine’s lack of antibiotics especially clever. Typically, drug development first involves the identification of a target. This is usually followed by multiple cycles of chemical synthesis, hit-to-lead optimisation, and formulation studies, along with various in silico approaches, to finally get a small molecule approved for a certain disease. Because the urgency of this problem means that conventional approach to drug discovery would be too slow, Laurie et al utilised the strategy of drug repurposing to find a quick solution to this problem. The rationale is that, given that the library of drugs are already in clinical use, they would already have been studied—the pharmacology would be well characterised and the toxicities widely reported. As such, they are good candidates that already have a significant headstart in the process of drug discovery.

I also liked how Laurie et al selected their toxicity assays carefully. First, the authors did not assume that nitroxoline would automatically be safe in vitro. This is entirely appropriate because the effective inhibitory concentrations against B. mandrillaris and those used clinically are likely to differ.  Second, cell lines selected in screening were also appropriate. Laurie et al selected two glial cell lines, as well as those which represent the liver and kidney in which drug toxicities commonly manifest.

Future directions and questions for authors

The fact that Laurie et al only found one promising candidate among the 2177 screened compounds underscores the difficulty in discovering novel effective antimicrobials. However, this preprint is promising both in the discovery of a candidate in filling the gap that patients desperately need, as well as in showing how the strategy of drug repurposing is useful in urgent clinical needs where time is lacking, such as the field of antimicrobials.

The findings of this paper are useful to generate hypotheses too. Given the extensive SAR study, further optimisation of the nitroxoline structure will be possible to create new small molecules. Elucidating the targets underlying nitroxoline’s mechanism of action may also yield new pathways from which dangerous amoeba infections can be targeted. This can be done in vitro using cell lines or in vivo using animal tests, the next logical step in repurposing nitroxoline.

This discussion leads to a few outstanding questions.

  • The 10-fold higher maximal plasma concentrations (Cmax) of nitroxoline compared to its in vitro IC50 was used to justify its likely success. Does this mean that the antimicrobial action of nitroxoline is likely to be concentration-dependent? If it is time-dependent, how much longer will nitroxoline last above the minimal effective concentration? How does the in vitro data in this preprint, combined with what is already known about nitroxoline in clinical use, impact its clinical importance in GAE?
  • It appears that a phenotypic SAR was conducted in this preprint. If so, how was the metal chelating abilities of the agents predicted? What role might metal chelating play in the antiamoebic action of nitroxoline? Is it still likely to be biofilm disruption, even in vivo?

References

[1]        Khan NA, Ong TYY and Siddiqui R (2017) Targeting Brain-Eating Amoebae Infections. ACS Chemical Neuroscience 8(4): 687-688.

 

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