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

Abstract

Neisseria meningitidis and Neisseria gonorrhoeae, two highly related species that may have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection, whereas for N. gonorrhoeae, there are only a limited number of antibiotics available. 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 N. lactamica, 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 where much lower sensitivity was found for the more distant Neisseriaceae (such as N. elongata or Kingella oralis) and completely unrelated species. A significant boron uptake by N. meningitidis cells was observed after incubation with 5 μM of NaBPh4, as measured by ICP-MS, suggesting that this drug candidate's target(s) could be located intracellularly or within the cell envelope. Furthermore, mutants with a slightly decreased susceptibility displayed an alteration 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.

The role of vaccines in combating antimicrobial resistance (AMR) bacteria

“…The human specificity of the pathogen is also a major drawback to studying it. An N. meningitidis B OMV-based vaccine has been evaluated against N. gonorrheae B in clinical trials and found to be only 31% effective ( Bernet et al, 2021 ). Several other vaccines against K. pneumoniae, P. aureginosa, S. enterica, and Shigella sp, are also being developed as already illustrated in Fig.…”

Vertebrate and Invertebrate Animal and New In Vitro Models for Studying Neisseria Biology

“…Mouse models have also been used to test the efficacy of antibacterial compounds. As an example, a model of meningococcal bacteraemia induced following intranasal infection with bacteria was used to demonstrate that administration of sodium tetraphenylborate could significantly reduce bacterial burden [ 223 ].…”

Sequential markerless genetic manipulations of species from the Neisseria genus

“…The markerless strains obtained here emitted a persistent luminescent signal. Of note, luminescent strains of N. meningitidis have been previously used successfully in murine infection models to measure bacterial burden (Alonso et al 2003;Zarantonelli et al 2007;Bernet et al 2020) and the markerless gene modification option is an added advantage.…”