Antimicrobials, Not Antibiotics
In a recent paper, researchers at NovaBay described a novel class of antimicrobial compounds known as N,N-dichloro-2,2-dimethyltaurines (Aganocides®), which are effective against MRSA and mupirocin-resistant Staphylococcus. Aganocides belong to a class of naturally occurring antimicrobial agents, the N-chlorotaurines, that operate within the human immune system and do not give rise to bacterial resistance of any kind.
The natural model for Aganocides, N-chlorotaurine, was described in 2000 as a novel agent for treating infectious conjunctivitis. A number of papers have been published using this compound as a topical antimicrobial agent. Nagl et al. reported the broad-spectrum biological activity of the long-lived oxidant N-chlorotaurine, which achieves 4-log reduction of bacterial and fungal pathogens at micromolar concentrations.
Biologists know that species related to N-chlorotaurine are responsible for up to 90% of the heavy lifting in bacterial clearance through white blood cell lysosomes. During oxidative bursts, hypochlorous acid is neutralized by taurine to form N-chlorotaurine, an oxidant that attacks and inactivates bacteria and other pathogens. N-chlorotaurine and the related N-dichlorotaurine possess broad-spectrum antimicrobial activity, but both degrade rapidly in the body and are labile in conventional pharmaceutical formulations. Aganocide compounds overcome this deficiency of the natural compounds through a chemical modification that renders them more stable.
Like their natural analogs, Aganocide compounds fight MRSA and other resistant Staphylococcus bacteria through the chloronium ion, a form of chlorine suitable for eradicating bacterial colonizations and infections on the skin, in other accessible areas of the body, and on some implantable medical devices. The Chloronium ion has been employed in water disinfection for at least 150 years.
Aganocides, which deliver an attenuated form of chloronium ion, are not antibiotics. Their mode of action is nonspecific and does not depend on cells being in reproductive phase. Aganocides do not inhibit cellular processes, DNA replication, enzymes, or any pathways that might, through evolutionary processes, adapt to their mode of action.
Rather, chloronium ions generated by Aganocides rapidly inactivate organisms by attacking sulfur- and nitrogen-containing amino acids on the bacterium’s surface. Microorganisms cannot adapt, either individually or through evolutionary processes, to this mode of action, which is not unlike being run over by a Sherman tank. Developing immunity to Aganocide compounds would require that MRSA bacteria completely change their chemical composition.
In this respect, Aganocides resemble antimicrobial peptides, another group of natural defense compounds that do not induce microbial resistance. Antimicrobial peptides are evolutionarily conserved, meaning their structures are similar across species and over millions of years of evolution. These agents are usually amphiphilic, allowing them to operate in aqueous environments yet also enter lipid-rich membranes. Unfortunately, no antimicrobial peptide or analog has proved to be commercially viable, since their selectivity for bacterial vs. mammalian membranes is too low.