538 JOURNAL OF COSMETIC SCIENCE
of co-discovering scientists Frederick Twort and Felix d’Herelle in the early 1900s, and
set them on a journey to translate this biological phenomenon into a method of disease
curtailment.21,25 Therefore, topical application of bacteriophages can diminish a single
problematic bacterial species without collateral damage to the surrounding microbes.
Bacteriophages are omnipresent in nature, literally occupying nearly every environmental
niche on the planet. Wherever the obligate host cells of bacteriophages are present—
Bacteria and Archaea—bacteriophages will be found. The fact bacteriophages replicate
inside of two of the three domains of cellular life, a rather stunning statistic has been
proposed that there are as many 1031 bacteriophage particles on Earth at any given time.26–28
Given this number, these bacterial viruses represent a vast, continually evolving, natural
resource for which to counter the most problematic of bacterial pathogens.
More than a century of researching bacteriophages has shown that they can be grouped into
one of two categories: lytic or lysogenic (Figure 1).25 The former represents bacteriophages
that rapidly replicate and assemble new viral particles upon infection of their host
bacterium. This precipitous build-up of new bacteriophages culminates in the lysis of the
bacterium from the inside out, spewing new bacteriophages into the surrounding tissue
to repeat the lytic cycle over again. In strong contrast, lysogenic bacteriophages enter into
a quiescent state once they have infected their bacterial host. During this static period,
the bacteriophage genomic material sometimes becomes incorporated into the bacterial
genome, which can cause the bacteria to evolve by what is known as transduction. The
utility of bacteriophages to counter diseases driven by bacterial pathogens is predicated on
selecting naturally occurring bacteriophages that exclusively follow the lytic cycle.
The extensive history associated with bacteriophage-based therapy boasts many clinical
success stories.29–31 d’Herelle’s first application of bacteriophage preparations to counter a
bacterial pathogen was in 1919, where he treated Shigella associated dysentery. The first
patient experienced improved health after a single dose with a full recovery reported a
Figure 1. Lytic cycle versus lysogeny. Schematic depicting the differing fates of phages upon infection of
their bacterial hosts is presented. They can either actively replicate and assemble new phage particles until the
host bacterium is lysed from the inside out (lytic cycle, left side of image), or they can enter into a quiescent
state whereby their genetic material lingers and can potentially be incorporated into the host bacterium’s
genome (lysogeny, right side of image).

539 Modern Skincare
few days later, which was followed by three additional clinical successes. Subsequently,
the first clinical use of bacteriophages in the United States (US) was described in
1922.29,32,33 Interestingly, the initial US case did not report a positive outcome, though the
circumstances of the study were called into question. However, follow-up studies indicated
considerable success in the treatment of bacterial diseases including skin and dental
infections. In 1931, such positive findings prompted three different US-based biomedical
companies to begin mass production of bacteriophages targeted to four different types
of bacteria. Despite several successes, there were also some confounding results that are
now understood to be based on a poor understanding of the biology of bacteriophages at
the time, particularly the distinction between lytic and lysogenic bacteriophage. Many of
these early shortcomings have since been explained and rectified by modern approaches.
An important point to stress is that for many of the clinical studies conducted with
bacteriophage therapy, there is a consistent safety profile with limited adverse effects
being reported in the studies.30,31,34
A profoundly important development in the collective understanding of bacteriophages in
modern times is that these viruses are a normal part of the human skin microbiome.35,36
Furthermore, there is a growing appreciation that their relative levels are different on
healthy skin versus skin with microbe-driven afflictions.37–39 Such correlations have been
observed with acne vulgaris, atopic dermatitis, and psoriasis. With the rise in topical
antibiotic resistance of particular bacterial species implicated in various skin conditions,
the utility of bacteriophages as an alternative means to mitigate the impact of these
microbial culprits becomes an attractive prospect. Two notable bacterial species where this
approach has been explored with some successes to tackle skin infections are: C. acnes and
S. aureus.40–45 Given the historical nature of bacteriophage therapy, it is interesting to note
that the isolation of the first bacteriophages targeting C. acnes dates back to 1964, then
known as Corynebacterium acnes.46
Here, the hunt for bacteriophages that predate upon C. acnes and S. aureus is described. The
methodical exploration of how the C. acnes bacteriophages were characterized and qualified
to counter C. acnes driven blemished skin is further detailed. Such examinations ranged
from simple laboratory testing to evaluations on three-dimensional skin models and in vivo
pilot studies.
RESULTS
HUNT FOR NATURAL BACTERIOPHAGES
Most bacteriophage (or phage) hunts entail the evaluation of environmental samples for
anti-microbial effects on cultures of the target bacterium of interest. Herein, phages
against two target bacteria were sought: Cutibacterium acnes and Staphylococcus aureus. When
phages were detected that countered each bacterial species, they were examined both
genetically via next-generation gene sequencing and structurally through transmission
electron microscopy (TEM). These examinations determined the family of viruses of
which the individual phage belonged. As shown below, all three phages identified that
affected a lytic cycle in C. acnes (Figure 2A) exhibited capsid structures indicative of the
family Siphoviridae. Members of this family of viruses are characterized by their long non-
contractile tails attached to an icosahedral head.24 Furthermore, bacteriophages known
to infect and lyse C. acnes have frequently been demonstrated to adopt virion structures