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Methicillin-resistant Staphylococcus aureus

(MRSA): antibiotic-resistance and the biofilm
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Cite this: Med. Chem. Commun.,

2019, 10, 1231 phenotype
Kelly M. Craft, Johny M. Nguyen, Lawrence J. Berg and Steven D. Townsend *

Staphylococcus aureus (S. aureus) is an asymptomatic colonizer of 30% of all human beings. While gener-
ally benign, antibiotic resistance contributes to the success of S. aureus as a human pathogen. Resistance
is rapidly evolved through a wide portfolio of mechanisms including horizontal gene transfer and chromo-
somal mutation. In addition to traditional resistance mechanisms, a special feature of S. aureus pathogene-
sis is its ability to survive on both biotic and abiotic surfaces in the biofilm state. Due to this characteristic,
S. aureus is a leading cause of human infection. Methicillin-resistant S. aureus (MRSA) in particular has
emerged as a widespread cause of both community- and hospital-acquired infections. Currently, MRSA is
Received 26th January 2019, responsible for 10-fold more infections than all multi-drug resistant (MDR) Gram-negative pathogens com-
Accepted 12th March 2019
bined. Recently, MRSA was classified by the World Health Organization (WHO) as one of twelve priority
pathogens that threaten human health. In this targeted mini-review, we discuss MRSA biofilm production,
DOI: 10.1039/c9md00044e
the relationship of biofilm production to antibiotic resistance, and front-line techniques to defeat the
rsc.li/medchemcomm biofilm-resistance system.

I. Introduction is impetigo, a highly contagious skin infection that appears

as red sores on the face near the mouth and nose. Other clin-
Nosocomial infections are a major global health concern.1–7 ical manifestations of staph infection include endocarditis,
While significant progress has been made preventing trans- osteoarticular infection, pneumonia, toxic shock syndrome,
mission, on any given day, approximately 5% of patients in and prosthetic device and catheter infections.22
developed countries and 10% of patients in developing coun- Staphylococcal infections occur when host defense mecha-
tries will acquire a hospital-associated infection (HAI).8–11 nisms are low as a result of debilitating illness, open wounds,
Higher rates of HAI are seen in developing countries due to or treatment with steroids or other drugs that compromise
limited resources.12,13 Furthermore, HAI rates can rise to immunity (Fig. 1). Indeed, S. aureus infection rates in ICUs
around 50% for patients in intensive care units (ICUs).14 are of particular concern, and the risk of infection increases
Staphylococcus aureus (S. aureus) is a common cause of with the duration of a patient's stay in these units.14,23,24 This
nosocomial infection.15–17 S. aureus is a Gram-positive com- characteristic of Staphylococcal infections is largely attribut-
mensal that persistently colonizes the skin and mucosae of able to the fact that S. aureus is an opportunistic pathogen
approximately 30% of the human population.18 Another 60% that possesses an extensive arsenal of virulence factors that
of people are transiently colonized.19 While the nose is the enable the organism to take advantage of a compromised
most frequent carriage site, the skin, axillae, perineum, and host.25,26 Moreover, a number of strains possess a battery of
pharynx are also common sites of colonization.20 resistance mechanisms against conventional antibiotics.27 To
While S. aureus appears as an innocuous commensal, it is compound the problem, S. aureus can live in the biofilm
responsible for a major infectious disease burden.18 As an state. Biofilms are organized populations of bacteria encapsu-
adaptable pathogen, S. aureus can cause a wide range of ill- lated in a self-produced extracellular polymeric matrix that
nesses after an open wound or “entry point” is inoculated.21 adheres to biotic and abiotic surfaces.28,29 Importantly, bio-
For example, the most common type of staph infection in films provide protection from antibiotics and the host im-
adults is the boil, a pocket of pus that develops in a hair folli- mune system. Additionally, bacteria in the biofilm state dis-
cle or an oil gland. In children, the most common infection play increased resistance to stress compared to those in the
planktonic state. Given the ability of biofilms to shield bacte-
ria from harsh host environments, biofilm adds an addi-
Department of Chemistry, Vanderbilt University, 7300 Stevenson Science Center, tional level of complexity to the problem of antimicrobial
Nashville, TN, 37235, USA. E-mail: steven.d.townsend@vanderbilt.edu resistance.

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Fig. 1 Scanning electron microscope (SEM) image of Staphylococcus

aureus-infected bone (image courtesy of Dr. Jennifer Gaddy at
Vanderbilt University).

II. Methicillin-resistant S. aureus

(MRSA)
Fig. 2 Mechanisms of Staphylococcus aureus resistance to penicillin
S. aureus is an adaptable organism with the ability to evolve (1), methicillin (3), and vancomycin (4). (A) Penicillin is inactivated by
resistance to an array of antibiotics. Resistance development bacterial β-lactamases that hydrolyze the β-lactam ring, which forms
and subsequent dissemination are consequences of horizon- an inactive penicilloic acid. (B) Resistance to methicillin, a modified-
penicillin scaffold featuring a larger aryl side chain that is resistant to
tal gene transfer (HGT), i.e. the lateral movement of genetic
β-lactamase action, is driven by the expression of the alternative trans-
information between organisms. Notably, HGT enables new, peptidase, PBP2a, which has a lower affinity for methicillin. Resistance
antibiotic-resistant variants to arise without the need for ge- to vancomycin results from modification of the terminal dipeptide of
netic mutation.30–32 This mode of action is often encountered cell wall peptidoglycan chains, which reduces the affinity of the dipep-
in hospitals where selective pressure for resistance is en- tide for vancomycin.

hanced. Inevitably, hospital-associated resistant strains enter

and spread throughout the community.
Antibiotic resistance in S. aureus was first observed in the PBPs are membrane-bound enzymes that catalyze the
1940s when infections caused by penicillin-resistant S. aureus cross-linking or transpeptidation reactions that link peptido-
(PRSA) emerged in hospitals.33,34 These strains produce a glycan chains in the bacterial cell wall.35 In the absence of re-
plasmid-encoded lactamase (penicillinase) capable of hydro- sistance mechanisms, β-lactams inhibit the transpeptidase
lyzing the β-lactam ring of penicillin (1). As this ring is the domain of PBPs. This results in inhibition of the cross-
antimicrobial warhead of penicillin, its hydrolysis renders linking reactions which are integral to formation of a stable
the drug inactive (2) (Fig. 2A). Within a few years after its ap- peptidoglycan layer. Without a structurally sound peptidogly-
pearance in hospitals, PRSA had spread to the community. can layer, bacterial cell walls become weak and lack the abil-
By the 1950s and 1960s, penicillin-resistant strains in the ity to contain the cytoplasmic contents of the cell.36 While
community had reached pandemic levels.33 Today, more than PBP2a shares the structural features associated with penicil-
90% of Staphylococcal isolates produce penicillinase and are lin binding that are common to other PBPs, PBP2a has a low
consequently resistant to penicillin.35 affinity for all β-lactams. Indeed, the PBP2a active site is able
In an attempt to combat penicillin resistance, methicillin to block the binding of β-lactams while simultaneously
(3) was introduced in 1959.33,34 Methicillin features a larger allowing cross-linking to proceed.35 Importantly, while
aryl moiety near the β-lactam ring which reduces its affinity β-lactamase-mediated resistance is a narrow-spectrum mech-
for Staphylococcal β-lactamases.36 Unfortunately, the first re- anism, i.e. only penicillin is inactivated by the enzyme, meth-
ports of methicillin resistance were observed in 1961, just 2 icillin resistance due to PBP2a expression is a broad-
years after methicillin's introduction. Contrary to penicillin spectrum resistance mechanism. All β-lactams, including
resistance, methicillin resistance is not a result of drug inacti- penicillins, cephalosporins, and carbapenems, are inactive
vation, i.e. hydrolysis of the β-lactam ring, but rather a result against bacterial strains expressing PBP2a.
of drug target modification (Fig. 2B). Methicillin-resistant S. The inability of β-lactams to combat staph infections has
aureus (MRSA) strains express an additional penicillin- led to an increased use of vancomycin (4) and the inevitable
binding protein (PBP), known as PBP2a, which has been hy- evolution of vancomycin-resistant S. aureus (VRSA) strains.37
pothesized to have originated from Staphylococcus sciuri.36 Similar to methicillin resistance, vancomycin resistant S.

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aureus strains derive their resistance from structural modifi- The first stage of biofilm formation is the attachment of a
cation of the target. Modification of the terminal dipeptide of bacterial cell to a living (biotic) or non-living (abiotic) surface
cell wall peptidoglycan chains from D-alanyl-D-alanine (D-Ala-D- (Fig. 4).45 Following attachment, bacteria in the biofilm state
Ala) to D-alanyl-D-lactate (D-Ala-D-Lac) reduces the affinity of progress through a growth and maturation phase.46 At the
the dipeptide for vancomycin, thus preventing disruption of molecular level, the biofilm matrix is composed of an extra-
peptidoglycan cross-linking (Fig. 2B).38 cellular polymeric substance (EPS) composed primarily of oli-
Today, MRSA is pandemic. The rise to pandemic status gosaccharides, DNA, and proteins.47 The primary oligosac-
started with hospital-acquired MRSA clones in the 1960s. charide in S. aureus biofilm matrices is a polymer of N-acetyl-
This then fostered community-acquired MRSA clones in the β-(1-6)-glucosamine (polysaccharide intercellular adhesin or
1990s and finally livestock-associated MRSA clones in the PIA), while the accumulation-associated protein (Aap) is a
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2000s. The evolution of MRSA from initial reports to wide- common biofilm-associated protein. Teichoic acids are also
spread dissemination parallels the trajectory of PRSA in the common biofilm components. At the end of the biofilm cycle,
1940s. Unsurprisingly, MRSA is highly prevalent in hospitals cell clusters detach from the larger biofilm structure. Detach-
(Fig. 3). The highest rates of MRSA (>50%) are reported in ment is facilitated by expression of surfactant-like peptides,
North and South America, Asia, and Malta. Intermediate which are also critical to biofilm integrity and three-
rates (25–50%) are reported in China, Australia, Africa, and dimensional structure. Once detached, cell clusters can start
several European countries [e.g. Portugal (49%), Greece new biofilm colonies on other surfaces.
(40%), Italy (37%) and Romania (34%)]. Most European coun- S. aureus pathogenesis and biofilm development is con-
tries have low prevalence rates (e.g. Netherlands and trolled by cell-to-cell communication using a ubiquitous regu-
Scandinavia).39–41 latory system called quorum sensing.48–52 During its growth
and maturation phase, S. aureus produces an autoinducing
peptide (AIP) that accumulates in the extracellular environ-
III. The biofilm state ment. Once AIP levels reach a specific concentration, the sig-
nal binds to a bacterial surface receptor and activates a regu-
Implantable medical devices have revolutionized modern latory cascade. The outcome is an increased expression of
healthcare. Unfortunately, attachment to indwelling devices invasive factors such as toxins, hemolysins, proteases, and
by surface-adhering bacteria increases patient morbidity and other tissue-degrading enzymes. Interestingly, these factors
mortality. Biofilms formed by Staphylococci are the most alter the metabolic status of the bacteria which subsequently
common cause of biofilm-associated infections with S. aureus changes their biofilm-forming capacity. Unfortunately, the re-
being among the most common cause of device related infec- lationship between environmental stress and pathogenesis
tions (DRI).42–44 All implanted medical devices are suscepti- remains poorly understood.
ble to colonization by Staphylococci. As a result, biofilm-
associated infections have been associated with devices such IV. Biofilm-mediated antimicrobial
as implanted catheters, prosthetic heart valves, cardiac pace-
makers, contact lenses, cerebrospinal fluid shunts, joint re- resistance
placements, and intravascular lines. To exacerbate the prob- It has long been recognized that biofilms increase resistance
lem, infections associated with biofilms are particularly to antimicrobial action from both external agents, such as
difficult to treat as bacteria within the matrix are more resis- antibiotics, and internal agents of the innate immune sys-
tant to antimicrobial agents and the host immune response tem, such as antimicrobial peptides (AMPs).53 Broadly speak-
than planktonic bacteria. This increased resistance is attrib- ing, two mechanisms are responsible for biofilm-mediated re-
utable both to the protection afforded by the biofilm matrix sistance. The first is prevention of chemotherapeutics from
as well as the unique phenotypic characteristics of bacteria reaching their target due to limited diffusion or repulsion
within the matrix. caused by the biofilm matrix itself.28,54 The second mecha-
nism involves alteration of the physiology of biofilm-dwelling
bacteria compared to planktonic bacteria.

Fig. 3 Global prevalence of hospital-acquired MRSA. Fig. 4 The biofilm life cycle.

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Cells within the biofilm, particularly those deep within the

matrix, are generally thought to exist in a slow-growing state;
these slow-growing cells are referred to as dormant or per-
sister cells. Persister cells are a small fraction of exponen-
tially growing cells, but are ca. 1% of bacteria in both the sta-
tionary phase and in biofilms. The decreased growth rate of
persister cells can limit the efficacy of antibiotics, especially
those that target active cell processes, without the need for
genetic alteration.55–57 For example, this type of cell would be
immune to β-lactams that target cell wall formation in ac-
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tively dividing cells.28,29,54 The ability of dormant cells to sur-

vive numerous rounds of antibiotic treatment also makes
them key contributors to the restoration of biofilm
communities.54

V. Strategies to combat MRSA

biofilms
The development of strategies to prevent, remove, or disperse
biofilms are as critical to treating staph infections as the devel-
opment of new antibiotics.58–63 A frontier approach in the bat-
tle against S. aureus is to develop anti-biofilm strategies that
can be combined with conventional antibiotics as a means to
restore antibiotic efficacy to levels observed when treating
planktonic bacteria. In this section, we will discuss several ap-
proaches used to eradicate MRSA biofilms. These strategies Fig. 5 Select antibiofilm small molecules.
can be broken down broadly into two categories: prevention of
biofilm formation (antibiotic chemotherapy, anti-adhesive
coatings/surfaces) and elimination of established S. aureus
biofilms. B. Physical methods for biofilm removal
Second to preventing initial infection and, by extension, ini-
A. Antibiotic therapy tial formation of a biofilm matrix, the next simplest method
to treat an S. aureus biofilm-mediated infection is through
The best method for treating a biofilm-related infection is by surgical removal of the biofilm abcess.67 Removal can occur
preventing initial infection altogether. Unfortunately, the fac- through debridement of wounds or surgical implants. Irriga-
ile evolution of antibiotic resistance by S. aureus poses a sig- tion and pulsed lavage are also strategies that are commonly
nificant challenge to this approach. Biofilms compound this employed. Unfortunately, techniques that apply purely physi-
issue by significantly increasing antibiotic minimum inhibi- cal tools have limited success. For example, pulse lavage irri-
tory concentrations (MICs) compared to cells in the plank- gation is ineffective at eliminating S. aureus biofilms present
tonic state.64 For example, the MIC for vancomycin, the most on indwelling devices.68
commonly administered drug for S. aureus biofilm-associated
infections, is 10-times higher for biofilm-bound cells than for
planktonic, free-floating cells (planktonic cell MIC = ca. 2 μg C. Attachment prevention
ml−1, biofilm bound cell MIC = ca. 20 μg ml−1).65 Attachment of bacteria to abiotic surfaces is mediated by a
Despite growing resistance levels, there do exist antibi- number of factors such as adhesion surface proteins, fim-
otics, such as daptomycin (5) that are effective at treating briae or pili, and exopolysaccharides.69,70 Adhesion occurs
even VRSA biofilm-related infections (Fig. 5). Daptomycin, a most readily on surfaces that are coarse or hydrophobic. As
cyclic lipopeptide molecule, is a novel antibiotic that disrupts hospitals are rich with these types of surfaces, hospitals are a
the cytoplasmic membrane via rapid depolarization and major source of device-associated infections. In a similar
interruption of DNA, RNA, and protein synthesis. Impor- vein, indwelling medical devices often feature coarse or hy-
tantly, daptomycin is one of the most effective antibiotics at drophobic surfaces and thus present another potential colo-
clearing S. aureus from an existing biofilm.66 Moreover, be- nization surface. Due to the prevalence of device-related in-
cause the mode of action for daptomycin does not require fections, there has been increased interest in developing anti-
cells to be in a metabolically active state, it is a particularly infective strategies to prevent colonization.71–74
useful agent in the fight against persister cells embedded While adhesion to abiotic surfaces, such as metal and plas-
deep within the biofilm matrix. tics, proceeds through nonspecific mechanisms, adherence to

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biotic surfaces is dependent on surface proteins that are an- Interestingly, although silver coatings are frequently used, the
chored to the cell wall peptidoglycan.75,76 Indeed, cell surface mechanism of action behind silver-mediated biofilm produc-
proteins, which are designed to recognize host surfaces, are tion prevention remains unknown. However, changes to bacte-
critical for S. aureus adherence to host tissues as well as sub- rial cell morphology have hinted at several mechanisms. For
sequent tissue colonization and ultimately the survival of example, silver nanoparticles have been shown to attach to the
MRSA infections. Surface proteins known to play important bacterial membrane and penetrate the cell. After gaining en-
roles in biofilm formation include Bap, clumping factors trance, the nanoparticles engage sulfide-containing proteins
(ClfB), FnBPs, SasC, SasG, and protein A. ClfB, FnBPs and pro- and DNA. This resultantly inhibits DNA replication and tran-
tein A are widely distributed.77–81 To target these proteins, scription. Thus, it is thought that silver prevents biofilm pro-
and thus disrupt attachment, the Clubb group used an array duction by serving as an antimicrobial agent.
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of small molecules to inhibit MRSA transpeptidase sortase A; While silver-coating is common, there are cytotoxicity con-
MRSA transpeptidase sortase A is a protein that anchors sur- cerns with this method. Silver accelerates thrombin forma-
face proteins to the cell wall.82,83 In theory, cell surface pro- tion and platelet activation which subsequently places pa-
teins are a novel therapeutic target to disrupt adhesion or ad- tients at higher risk for thrombosis. To avoid this issue,
herence and mitigate biofilm formation. stainless steel and titanium have also been used to coat im-
Whether dealing with biotic or abiotic surfaces, the fron- plant materials.91–93 Interestingly, a number of medical de-
tier challenge in attachment prevention methods remains un- vices have also been coated with vancomycin to prevent
derstanding how bacteria coordinate the expression of differ- MRSA adherence.
ent effectors and how various surfaces, particularly cellular
surfaces, react to these effectors. If this communication sys-
tem can be deciphered, one can develop strategies to eradi- D. Treatment or dispersal of established biofilms
cate biofilms by blocking initial adherence of the microbe. In D1. Small molecules. Cis-2-Decenoic acid (C2DA, 7) is a
the proceeding sections, several coatings that prevent bacte- medium-chain fatty acid produced by Pseudomonas aeruginosa
rial attachment to and growth on surfaces are described. that has been shown not only to possess the ability to disperse
C1. Small molecules. Aryl rhodanines (6) are 5-membered established MRSA biofilms but also to completely inhibit
ring heterocycles that are known to inhibit biofilm formation MRSA biofilm formation (Fig. 5).94,95 In addition to this lipid,
in several Gram-positive models, including Staphylococcal it has been shown that D-amino acids disperse established
and Enterococcal species (Fig. 5).84 Aryl rhodanines function biofilms in S. aureus. Incorporation of D-amino acids into the
by inhibiting attachment of bacterial cells through a mecha- peptidoglycan layer results in the release of amyloid fibers, a
nism that likely involves complexation of the rhodanines to component of the extracellular matrix that connects cells in
one or more adhesins located on the microbial cell surface. the biofilm matrix.96–99 Kolodkin-Gal demonstrated that
Interestingly, aryl rhodanines are inactive against Gram- D-amino acids disperse Bacillus subtilis biofilms by affecting
negative microbes. Importantly, while rhodanines possess the function of these amyloid fibers.100 Mechanistically, when
anti-biofilm activity, they do not possess antimicrobial activ- noncanonical amino acids are incorporated into the peptido-
ity and are not cytotoxic against human cells. From a thera- glycan layer, they interfere with the normal anchoring that
peutic perspective, rhodanines have the potential to be im- helps maintain biofilm architecture integrity. Moreover,
portant tools in the battle against MRSA as their lack of D-amino acids compete with canonical amino acids for posi-
antimicrobial activity reduces selective pressure. In other tions in the peptidoglycan layer which interferes with trans-
words, this class of small molecule is less likely to produce peptidation and transglycosylation. Importantly, this disrup-
resistant strains or to induce high levels of biofilm produc- tion of bacterial cell wall composition caused by D-amino acid
tion as a means to protect against a strong antimicrobial incorporation interferes with biofilm formation (Fig. 6).
substance. D2. Matrix degrading enzymes. Disruption of biofilm ma-
C2. Abiotic surface coating. Catheters coated with tetracy- trix structural integrity is an attractive approach to limit the
clines and ansamycins, both of which are bacteriostatic as protective effects the matrix affords cells enclosed within it.
opposed to bactericidal antibiotics, have been shown to de- This method is the reason for the addition of exogenous
crease the frequency of MRSA central line-associated blood-
stream infection (CLABSI) in ICUs.85,86 This result suggests
that alteration of the surface properties of an indwelling de-
vice by coating the surface with bacteriostatic agents can pre-
vent biofilm-associated infections.
A number of metals have also been used to coat abiotic sur-
faces, such as catheters, in an effort to prevent biofilm forma-
tion.87 The most well-known example is silver in the form of el-
emental silver, silver ions, and/or silver nanoparticles.88–90
Silver is effective at preventing biofilm formation against both
Gram-positive and Gram-negative microbes, including MRSA. Fig. 6 General methods for biofilm dispersal.

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enzymes, such as dispersion B or DNAase, to S. aureus Indicative of the benefit of biofilm production for S. au-
biofilms.101–104 DNAase works by degrading the extracellular reus survival, most chronic MRSA infections leverage the bio-
DNA in the biofilm matrix EPS, while dispersin B targets the film state in their pathogenesis. This is especially true for
polysaccharide EPS component. As biofilm matrices consist those associated with indwelling medical devices. As most
largely of extracellular DNA and polysaccharides, the actions therapeutic strategies are only effective at treating planktonic
of dispersin B and DNase serve to destabilize the matrix. It is cells or acute infections, there is an urgent need to develop
important to note, however, that the use of exogenous en- new therapeutic strategies capable of targeting S. aureus in
zymes like as dispersin B and DNase to disrupt S. aureus bio- the biofilm state. Unfortunately, despite much effort, the de-
film formation does have its shortcomings. For example, the velopment of useful biofilm inhibitors and/or dispersal
susceptibility of S. aureus to dispersin B differs significantly agents for Staphylococcal biofilms is in its infancy. While
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among strains. Moreover, a number of clinically relevant many innovative approaches to eradicate S. aureus biofilms
MRSA strains produce biofilms that contain little polysaccha- have been achieved over the past two decades such as small
ride which serves to limit the influence of dispersin B treat- molecules that prevent biofilm formation, enzymes that
ment on biofilm production. weaken biofilm matrix structural integrity, and antibodies
D3. Plant-derived natural compounds. Natural products and vaccines that target specific biofilm life cycle stages,
are critical to the discovery and development of new anti- these approaches lack clinical validation.
infective agents against MRSA.59–62 For example, extracts One potential future source of antibiofilm compounds are
from the broths of Krameria, Aesculus hippocastanum, and cationic small molecules. Indeed, several recent studies have
Conopodium majus each contains four compounds that have showcased the ability of positively-charged molecules to dis-
all been shown to inhibit S. aureus biofilm formation: rupt biofilm matrices and inhibit biofilm formation by a
chelerythrine (8), dihydroxybenzofuran (9), sanguinarine (10), number of pathogens.114–119 However, the antibiofilm activity
and proanthocyanidin (11) (Fig. 5).105 American cranberry ex- of this class of molecule is generally accompanied by antimi-
tracts, which contain proanthocyanidins (PAC), have also crobial activity. Although this may seem beneficial, the anti-
been shown to inhibit S. aureus biofilm formation as well as microbial activity is likely to induce selective pressure and
S. aureus growth.106,107 Moreover, polyphenolic compounds promote the evolution of resistant bacteria. Additionally, care
found in plant tissues, such as tannic acid (12), are known to must be taken with cationic molecules to limit cytotoxicity to
inhibit S. aureus biofilm formation (Fig. 5).108,109 mammalian cells. Given these concerns, identifying cationic
Tea-tree oil, an essential oil extracted from the leaves of small molecules with exclusive antibiofilm activity represents
Melaleuca alternifolia, eradicates biofilm production by S. au- an exciting research avenue.
reus, including MRSA, by damaging the extracellular ma- Another approach, one which our lab has begun to investi-
trix.110,111 This damage initiates subsequent removal of the gate, is to use host defense mechanisms as a source of molec-
biofilm from biotic surfaces. Ellagic acid (13) derivatives from ular inspiration. We recently demonstrated that human milk
Rubus ulmifolius limit S. aureus biofilm production and also oligosaccharides (HMOs), non-conjugated oligosaccharides
enhance the susceptibility of S. aureus to the antibiotics abundant in human milk, modulate growth and biofilm pro-
daptomycin, clindamycin, and oxacillin without contaminant duction for several bacterial pathogens, including MRSA.120
cytotoxicity to mammalian cells (Fig. 5).112,113 However, we have yet to identify the mechanism of action be-
Although the agents discussed in the section are effective hind the antibiofilm activity observed. In a parallel study, we
at combatting biofilms, their modes of action remain unclear. discovered that conversion of the ubiquitous HMO 2′-
fucosyllactose (2′-FL) to an anomeric, amino-variant gave a
Conclusion and future outlook compound with impressive antibiofilm activity against Group
B Streptococcus.121 Once again, the mechanism behind this
Rising MRSA infection rates pose a significant threat to hu- antibiofilm activity remains unknown. Thus, future studies
man health. While increasing antibiotic resistance is a well- are directed at elucidating a mechanism of action as well as
appreciated contributing factor, a lesser appreciated but investigating if this result translates to an S. aureus model.
equally important factor is the ability of S. aureus to form In addition to these approaches, as previously mentioned,
biofilms. Biofilms serve to protect S. aureus from host de- further elucidation of how bacteria coordinate the expression
fenses and antibiotics alike and are consequently integral to of various effectors and how surfaces react with these effec-
S. aureus pathogenesis. Indeed, biofilm-dwelling bacteria are tors will be paramount to the development of antibiofilm
generally able to tolerate much higher antibiotic concentra- compounds. Indeed, a greater understanding of this commu-
tions than their planktonic counterparts. The increased resis- nication system has the potential to identify unique bacterial
tance of biofilm-associated bacteria against antimicrobial ac- targets that can be engaged to target biofilm production se-
tion is attributable to the physical barrier between bacteria lectively without accompanying antimicrobial activity.
and antimicrobial afforded by the biofilm matrix as well as
the phenotypic shift bacteria embedded in the matrix un- Conflicts of interest
dergo. As a result, biofilm-associated infections are notori-
ously difficult to eradicate. There are no conflicts to declare.

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Acknowledgements of paediatric data from the European Centre for Disease

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FrieslandCampina, and the National Science Foundation (CA- fections in long-term care facilities for the elderly in Japan,
REER Award to SDT: CHE-1847804). K. M. C. is supported by J. Infect. Chemother., 2018, 24(5), 347–352.
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