Sodium Tetraphenylborate Displays Selective Bactericidal Activity against Neisseria meningitidis and N. gonorrhoeae and Is Effective at Reducing Bacterial Infection Load

Abstract

ABSTRACT Neisseria meningitidis and Neisseria gonorrhoeae, two highly related species that might have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection, whereas there are only a limited number of antibiotics available for N. gonorrhoeae. Unfortunately, some strains of these species are rapidly evolving and capable of escaping human interventions. Thus, it is now urgent to develop new avenues to fight these bacteria. This study reports that a boron-based salt, sodium tetraphenylborate (NaBPh4), displays high bactericidal activity and remarkable specificity against N. meningitidis and N. gonorrhoeae. Other closely related commensal species such as Neisseria lactamica, which is found in the normal flora of healthy individuals, were found to be less affected even at 5-fold higher doses of NaBPh4. This specificity was further observed when much lower sensitivity was found for more distant Neisseriaceae species (such as Neisseria elongata or Kingella oralis) and completely unrelated species. Significant boron uptake by N. meningitidis cells was observed after incubation with 5 μM NaBPh4, as measured by inductively coupled plasma mass spectrometry, suggesting that this drug candidate’s target(s) could be located intracellularly or within the cell envelope. Furthermore, mutants with slightly decreased susceptibility displayed alterations in genes coding for cell envelope elements, which reduced their virulence in an animal model of infection. Finally, a single dose of NaBPh4 resulted in a significant reduction in bacterial burden in a mouse model of N. meningitidis bacteremia. Although numerous boron-containing species were previously reported for their complex biological activities, the observation of this narrow selectivity is unprecedented and of potential importance from a therapeutic standpoint.