Abstract
To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disruption by PHMB, we observed cell entry into a range of bacterial species, and treated bacteria displayed cell division arrest and chromosome condensation, suggesting DNA binding as an alternative antimicrobial mechanism. A DNA-level mechanism was confirmed by observations that PHMB formed nanoparticles when mixed with isolated bacterial chromosomal DNA and its effects on growth were suppressed by pairwise combination with the DNA binding ligand Hoechst 33258. PHMB also entered mammalian cells, but was trapped within endosomes and excluded from nuclei. Therefore, PHMB displays differential access to bacterial and mammalian cellular DNA and selectively binds and condenses bacterial chromosomes. Because acquired resistance to PHMB has not been reported, selective chromosome condensation provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance.
Highlights
The broad-spectrum antimicrobial biocide polyhexamethylene biguanide (PHMB; polyhexanide) kills bacteria, fungi, parasites and certain viruses with a high therapeutic index[1]; it is widely used in clinics, homes and industry[2] (Supplementary Table 1)
To assess cell barrier damage that could be invisible to microscopy, E. coli K-12 cultures were grown to mid-log phase, treated with PHMB in the presence of the fluores
To test whether PHMB-mediated effects on cell elongation and chromosome condensation are altered by mutations to the SOS response pathway, we evaluated morphological responses in three mutant E. coli strains
Summary
The broad-spectrum antimicrobial biocide polyhexamethylene biguanide (PHMB; polyhexanide) kills bacteria, fungi, parasites and certain viruses with a high therapeutic index[1]; it is widely used in clinics, homes and industry[2] (Supplementary Table 1). It is most commonly used as a biocide, but is an important drug used in several topical applications. The prevailing model for PHMB’s microbe-selective toxicity holds that PHMB disrupts microbial membranes preferentially. To re-examine its mechanism(s) of action, we subjected PHMB to cellular, molecular and biophysical analysis, using both bacterial and mammalian cell systems. The outcome suggests a new model to explain its selective antimicrobial activities
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