The role of histones in innate immunity and anti-bacterial defense has been an ongoing puzzle: on the one hand, histones were originally reported to be anti-microbial agents, and the central importance of histones in the antimicrobial activity of neutrophil extracellular traps (NETS) is well established. On the other hand, histones have minimal antimicrobial activity under physiological conditions in vitro, and seem only to kill bacteria under artificial low magnesium conditions. How to reconcile these two contradictory sets of observations has until now remained a mystery. However, new work by Doolin et al. (http://doi.org/10.1038/s41467-020-17699-z) has finally solved a missing piece of the puzzle in a satisfying way: histones very limited antimicrobial activity by themselves. Rather, not only are they frequently found together with anti-microbial peptides (AMPs) in vivo, but they function together with AMPs in a synergistic manner.
How does the synergism work? Part of the mechanism is due to AMPs, which form pores in the bacterial membrane. These pores enable histones to enter the bacterial cytoplasm, where they are effective at inhibiting growth by perturbing chromosome organization and altering/impairing bacterial transcription. However, the synergy also involves the activity of histones at the bacterial membrane. Surprisingly, the AMP-induced pores are not stable, and once perforated, bacteria can recover from the effects of AMPs. Intriguingly, histones stabilize AMP-induced pores, blocking the bacterial healing process. This has multiple far-reaching consequences. First, by keeping the pores open, the proton-motive force gradient is destroyed, preventing ATP production and leading to effective energy loss in bacteria. Second, keeping the pores open leads to dramatic loss of bacterial cytoplasm (Fig. 1), which is extremely stressful, and certainly also prevents further effective bacterial growth. Finally, by stabilizing the pores, the histones promote increased entry of additional histones and AMPs into the bacterial cytoplasm. This gives rise to a positive feedback loop that exponentially amplifies the concentrations AMPs and histones inside the cytoplasm. The multiple avenues for histone and AMP synergies and interactions are summarized in Fig. 2.
While the discovery of this new synergism is intriguing and helps solve the long-standing problem of how histones are antimicrobial, it may also provide important clues for new antibiotic approaches. Importantly, there are pore-forming antibiotics such as the last-resort drug polymyxin B, and other classes of antibiotics, which are ineffective in healthcare settings due to the rise of resistant bacterial strains. However, as discussed in the new work, the synergistic activity of histones and AMPs leads to a self-amplifying cascade, where AMPs increase histone’s efficacy, and vice versa. This leads to the intriguing possibility that the utility of such pore-forming antibiotics could be re-invigorated by combining their activity with histones. Indeed, the paper finds strong synergy between histones and polymyxin B, supporting this as an exciting possibility for future work to explore.
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