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. 2026 Jun 16;14(7):e00613-26. doi: 10.1128/spectrum.00613-26

Antibacterial activity of glycerol monolaurate formulated in petrolatum

Patrick M Schlievert 1,✉, Angie Castillo-Zhagui 1, Samuel H Kilgore 1, Donald Y M Leung 2
Editor: Ryan S Doster3
PMCID: PMC13339809  PMID: 42300754

ABSTRACT

Glycerol monolaurate (GML) is a fatty acid monoester of glycerol that is approved by the FDA as a food additive and component of cosmetics. We previously showed that 50,000 µg/mL of GML solubilized in the non-aqueous K-Y Warming Gel is broadly antibacterial, including S. aureus and various streptococcal species, and selectively increases beneficial lactobacilli. GML is also anti-inflammatory, reducing harmful inflammation. In the current study, we examined GML and longer or shorter fatty acid monoesters for their anti-staphylococcal activity. GML had the greatest anti-staphylococcal activity. We then showed in vitro that GML solubilized in petrolatum, a non-aqueous gel that has fewer unwanted side effects than K-Y Warming Gel, had enhanced activity in the killing of both methicillin-sensitive and methicillin-resistant S. aureus. GML in petrolatum also killed two coagulase-negative staphylococci. Collectively, all staphylococci were killed by GML concentrations of ≥500 µg/mL. This concentration is 100 times below the concentration of GML we previously used in vivo in humans as solubilized in K-Y Warming Gel. GML in petrolatum also effectively killed four viridans streptococci, organisms increasingly recognized as pathogenic in atopic dermatitis in children. GML (50,000 µg/mL) in petrolatum was bactericidal for S. aureus as tested in a dermatitis model in rabbits. The data suggest that GML in petrolatum, upon additional testing, may become useful in topical management of nasal and skin colonization of children, as well as older individuals, with S. aureus and viridans streptococci, and for use in management of Gram-positive bacteria in atopic dermatitis and diabetic ulcers.

IMPORTANCE

Most staphylococcal and streptococcal infections in humans originate from mucous membranes, usually the anterior nares, or from the skin. Glycerol monolaurate (GML) solubilized in petrolatum exhibited potent anti-Gram-positive bacteria activity as tested both in vitro and in a staphylococcal rabbit skin model. Because GML is generally recognized as safe (GRAS by FDA) and petrolatum is already approved for topical human use, our data suggest that upon additional testing GML in petrolatum may be effective for topical use in management of nasal and skin colonization with S. aureus and viridans streptococci in young children (as well as older individuals), and for use in management of bacterial infections in atopic dermatitis and diabetic ulcers.

KEYWORDS: Staphylococcus aureus, viridans streptococci, lactobacilli, glycerol monolaurate, petrolatum, atopic dermatitis, diabetic ulcers, food allergies

INTRODUCTION

Glycerol monolaurate (GML) is a fatty acid monoester of glycerol and the 12-carbon fatty acid lauric acid. GML is generally recognized as safe (GRAS) by the Food and Drug Administration as a food additive and for use in cosmetics. GML is potently antimicrobial, killing Gram-positive bacteria, Gram-negative bacteria with a lipo-oligosaccharide outer membrane instead of full lipopolysaccharide, enveloped viruses, and fungi (1–5). GML solubilized in K-Y Warming Gel has been used to decolonize the anterior nares of S. aureus, a common source of the organism on the skin of patients (6). Further, a clinical study has shown that human breast milk can be used to reduce the symptoms of atopic dermatitis (AD) in children (7); human breast milk is one of only two sites in humans (8, 9) that contain GML, where it is strongly antimicrobial (8). The second site of GML presence in humans is within macrophages stimulated by certain intracellular pathogenic bacteria (9). The mechanism of antibacterial activity of GML correlates with its ability to embed into bacterial membranes and dissipate potential differences across the membranes (3), a property shared with a natural analog, reutericyclin, produced by many lactobacilli (10).

GML is also anti-inflammatory, reducing harmful inflammation (11, 12). Many pathogens cause infections in humans, primarily by disruption of mucosal and skin barriers (1, 2, 13). This suggests that the anti-inflammatory activity, in addition to antimicrobial activity, is important in preventing infections.

Our studies have shown that GML is synergistic in antibacterial activity in the presence of the non-aqueous gel, K-Y Warming Gel, compared with GML alone (3). This raises the possibility that GML can be solubilized in other non-aqueous gels with fewer adverse effects than K-Y Warming Gel. For example, some women, who have been treated with 5% GML in K-Y Warming Gel, experience stinging upon initial application, and the warming property of K-Y Warming Gel depends on partial dehydration of the epithelium (14).

Petrolatum appears to be a milder solubilizing agent for GML. This agent is a semi-solid mixture of hydrocarbons, such as mineral oils and waxes. Petrolatum is commonly used as a mild, but effective, protective skin barrier treatment to prevent water loss. For example, petrolatum is often used on chapped skin associated with rhinorrhea (runny nose) and diaper rash.

AD is a chronic inflammatory condition that mainly affects the skin (15, 16). AD is characterized by chronic itching, scratching and consequent rash development. AD is one of the most common skin conditions and is present in approximately 204 million people globally. Within the U.S., approximately 32 million people have AD. The onset of AD begins most often in children who are between the ages of 2 months to 5 years (17, 18). Additionally, an AD diagnosis may be one of the first steps in a process some investigators refer to as the “atopic march” (18–20). The “atopic march” often begins with AD, followed by food allergy, allergic rhinitis, and eventually asthma. AD may become less severe as a child ages and enters adolescence. However, there are many cases of AD in adulthood.

Patients with AD are susceptible to colonization and infection by Gram-positive bacteria, notably Staphylococcus aureus (16). AD in very young children is increasingly being associated with viridans streptococci (21). S. aureus is present on the skin of 17% of adults, and for those with AD, the percentage becomes 100% (16). Viridans streptococci are commonly present on the skin of very young children (21). While S. aureus may reside naturally in the human flora, most often originating from the anterior nares, patients with AD are infected on their skin by S. aureus (16). S. aureus, and its secreted toxins, play key roles in driving the symptoms of AD (16, 22, 23), including intense itchiness, and inflammation within skin lesions. For very young children, viridans streptococci may function similarly to S. aureus, though these organisms lack many of the potent exotoxins of S. aureus. For example, viridans streptococci lack known superantigens, cytotoxins, and lipases. However, they produce potent proteases similar to S. aureus. Proteases have been suggested to contribute to the intense itching in AD (22).

There are many other types of S. aureus infections. S. aureus skin infections are common also (i) in otherwise healthy persons in the form of soft tissue skin infections and (ii) skin infections and diabetic ulcers in association with diabetes mellitus types 1 and 2 (>30 million persons yearly in the United States) (15, 24–26). In hospitals, clonal group USA100 strains, methicillin-sensitive S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA) are common. USA200 strains, all of which produce the superantigen toxic shock syndrome toxin-1 (TSST-1), are 95% of the time restricted to mucosal surfaces unless the patient has damaged skin (15). The remaining 5% produce wild-type amounts of the cytotoxin α-toxin and can directly infect intact skin. USA300 and USA400 strains are also common (27–29), though USA300 strains are becoming less common; S. aureus strains cycle through communities and hospitals in roughly 10-year intervals (30). Both of these latter clonal groups (USA300 and USA400) are typically skin-associated strains, that are mostly MRSA, causing impressive skin infections. USA100-400 strains may spread from skin or mucosal surfaces to cause highly fatal hemorrhagic pneumonia. Other USA clonal groups (USA500–USA1100) can also be associated with skin infections (31).

S. aureus skin infections in diabetes mellitus patients are exceptionally common (15, 25). Obesity and pre-diabetes mellitus type 2 increase S. aureus skin infections, approaching 100% when people develop diabetes 2 (25). We have evaluated nine people with diabetes mellitus type 2 for the presence of S. aureus (25). Based on swabbing their palm, forearm, and axillary skin surfaces, these people have 1011–1013S. aureus on their total skin surfaces, or up to 1 cubic inch. The isolated S. aureus were MRSA and MSSA and produced the superantigens enterotoxin C (SEC) and toxic shock syndrome toxin-1 (TSST-1). Two of the patients ultimately succumbed to septic infections due to the same S. aureus that colonized their skin. Also, we and others have shown that the superantigens of S. aureus have the ability to induce diabetes mellitus type two changes in experimental animals and human adipocytes (25, 26, 32). Diabetes mellitus-associated foot ulcers are severe complications of diabetes (33). These lesions are exceptionally difficult to heal, and they easily become infected with S. aureus, leading to amputations in patients with uncontrolled diabetes.

This study was undertaken to examine the ability of GML alone and GML solubilized in petrolatum to kill various species of staphylococci, including both coagulase-positive S. aureus and coagulase-negatives (S. epidermidis and S. capitis), and viridans streptococci. We show that all staphylococci and viridans streptococci tested were killed by GML. However, in the presence of petrolatum, GML is significantly more active than GML alone. This suggests that GML in petrolatum upon additional testing could be an effective topical therapeutic to help in preventing and managing skin conditions due to these Gram-positive bacteria.

RESULTS

Solubilization of GML in petrolatum

Food-grade GML was solubilized in petrolatum (both petrolatum and generic) at GML concentrations as high as 5% (50,000 µg/mL). Both GML and petrolatum were stable at 65°C, the temperature used to solubilize GML. Petrolatum is a semi-solid at room temperature but is a liquid at 65 °C. After solubilization of 5% GML in petrolatum, the mixture could be stored at room temperature without GML crystallizing out of solution. This is different from 5% GML in K-Y Warming Gel where GML begins to crystallize out of solution at room temperature. The 5% amount of GML was chosen for the highest concentration studied since this was the highest concentration of GML used in pilot and clinical trial studies in K-Y Warming Gel as tested in adults, either on vaginal or nasal mucosa (6, 14).

Anti-S. aureus activity of fatty acid monoesters

We have previously published multiple studies of the anti-staphylococcal and anti-streptococcal activity of GML (3, 34, 35). We have not previously assessed other fatty acid monoesters. We thus evaluated GML (12-carbon side chain) compared with glycerol monocaprylate (8-carbon side chain), glycerol monocaprate (10-carbon side chain), and glycerol monomyristate (14-carbon side chain) for ability to kill S. aureus after 24-h incubation in Todd Hewitt broth growth medium. Because the molecular weight of each compound differs, the data were reported in mM (Fig. 1). GML was the most anti-staphylococcal with 1 mM yielding no S. aureus. The other fatty acid monoesters were also anti-staphylococcal with 4 mM glycerol monocaprylate yielding no S. aureus, 8 mM glycerol monomyristate yielding no S. aureus, and 16 mM glycerol monocaprate yielding no S. aureus. All of our subsequent studies evaluated only GML for activity since it was the most potent against S. aureus, and data were reported as micrograms per milliliter required for bactericidal activity. It is also important to note that all S. aureus strains produce glycerol ester hydrolase (lipase) with the capability to cleave the tested monoesters (36). The greater GML activity in the presence of S. aureus lipases suggests our next studies with GML may be the most important for development of topical-use antimicrobial monoesters.

Fig 1.

Line graph showing CFU reductions for four glycerol monoesters against S. aureus. Laurate requires the lowest concentration for kill, followed by caprate, myristate, and caprylate needing the highest.

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Anti-S. aureus activity in Todd Hewitt broth of glycerol monoesters (glycerol monolaurate [GML], glycerol monocaprate [caprate], glycerol monomyristate [myristate], and glycerol monocaprylate [caprylate]). Numbers in parentheses are fatty acid side chain lengths of the monoesters. Data are reported as log10 colony-forming units (CFUs)/mL ± standard deviation (SD) after 24-h incubation with S. aureus MN8 (inoculum size 9.8 × 106/mL).

Anti-S. aureus activity of GML alone, petrolatum alone, and GML + petrolatum

We previously published that GML alone is bactericidal for toxic shock syndrome (TSS) S. aureus strain MN8 (3, 34, 37). This organism is typical of menstrual TSS organisms in that it is positive for TSS toxin-1 (TSST-1), is methicillin-sensitive, and belongs to clonal group USA200 (CC30) (38). GML alone killed S. aureus MN8 by >3 log at average concentrations of ≥300 µg/mL (0.03%) in Todd Hewitt growth medium (3, 34, 37). With this as background, we evaluated GML alone, petrolatum alone, and petrolatum + various concentrations of GML (Fig. 2). We evaluated both methicillin-sensitive S. aureus (MN8 [USA200], MNPE [USA200], FRI1169 [USA200], HP1 [USA300-related]), and MNKN (USA400) and MNWH (USA200) both methicillin-resistant S. aureus (MRSA).

Fig 2.

Line graphs showing log CFUs/mL for six S. aureus strains treated with GML in petrolatum versus GML in PBS across concentrations of 0 to 500 µg/mL. Petrolatum formulation shows steeper bacterial reduction at lower GML doses.

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Anti-S. aureus activity of glycerol monolaurate (GML) in phosphate-buffered saline (GML in PBS; red bars) versus GML in petrolatum (GML in petrolatum; black bars). Data shown are log10 colony-forming units (CFUs)/mL ± standard deviations (SDs). Treatment groups list the µg/mL of GML in either phosphate-buffered saline or petrolatum. With use of Student’s t-test analysis of unpaired data, the means for GML in petrolatum versus GML in PBS at GML concentrations of 25, 50, and 100 µg/mL were significantly different with P < 0.001 for strains MN8, MNKN, MNWH, and MNPE. The means for GML in petrolatum versus GML in PBS at GML concentrations of 50 and 100 µg/mL were significantly different with at P < 0.001 for strains HP1 and FRI1169. The other means (GML) were not different (P > 0.05).

These experiments were performed with GML in petrolatum or PBS, the latter where GML has a solubility limit of 100 µg/mL. However, we previously showed that GML exerts it anti-staphylococcal effect at concentrations well above the solubility limit (3, 34, 37). We assume this results as progressively more GML becomes embedded in the bacterial membrane, and additional GML can then become solubilized. We define bactericidal as the reduction by ≥3 log10 CFUs/mL. GML alone in PBS was bactericidal for S. aureus only at approximately 500 µg/mL, versus 50 (for some S. aureus strains), 100, and 500 µg/mL for GML + petrolatum. Complete killing of S. aureus by GML alone in PBS or GML in petrolatum was observed at 500 µg/mL. Petrolatum alone was not antimicrobial for S. aureus over the 24-h test period.

We also performed a time-course experiment for GML in petrolatum to kill S. aureus MN8 (Fig. 3). GML in petrolatum was bactericidal by 1 h post-inoculation (P < 0.0002) compared with the zero time, with complete killing by 2 h.

Fig 3.

Bar chart showing S. aureus MN8 log CFUs per mL dropping from about 6.2 at hour 0 to roughly 3 at hour 1, then near 1 by hour 2, remaining at that level through hours 4 and 6.

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Time-course for killing of S. aureus MN8 by GML (500 µg/mL) in petrolatum. SD = standard deviation.

We previously showed that 5% (50,000 µg/mL) of GML in K-Y Warming Gel was effective in treating dermatitis in a rabbit model (39). K-Y Warming Gel gets its warming name from pulling moisture out of mucosal tissues, leading to a warm sensation, but at the same time potentially increasing drying. This latter property would be expected to reduce its use with GML, particularly in children. Thus, we evaluated 5% GML (50,000 µg/mL) in petrolatum, compared with petrolatum alone for treating S. aureus MN8 dermatitis in rabbits (Fig. 4). Rabbits, 4/group were challenged on flanks with 1 × 109 CFUs/0.1 mL in a 2 × 2 cm area. The flanks were then swabbed with GML + petrolatum, compared with petrolatum alone. CFUs/0.1 mL were determined after 8 h. GML + petrolatum led to complete elimination of S. aureus MN8, whereas petrolatum alone led to no reduction in S. aureus MN8.

Fig 4.

Bar chart showing S. aureus CFUs per mL near log 9 with petrolatum alone, dropping to near log 1 with petrolatum plus GML treatment after 8 h.

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Treatment of New Zealand white rabbits (4/group) on their shaved flanks with either 0.5 mL of petrolatum or 0.5 ml of 50,000 µg/mL of GML (5%) in petrolatum after exposure to approximately 1 × 109 S. aureus MN8 in a 0.1 mL volume (2 × 2 cm area). CFUs/mL ± standard deviation (SD) was determined after 8 h. Mean differences between the two groups was P < 6.4 × 10−9.

Effect of GML + petrolatum effect on Lactobacillus crispatus and coagulase-negative staphylococci

We have previously shown in vitro, in vivo vaginally in rhesus macaques, and in vivo vaginally in women, that GML (5%, 50,000 µg/mL) +K-Y Warming Gel led to no killing of lactobacilli, and indeed, led to increases in normal microbiome lactobacilli vaginally in women (1, 2, 5, 14, 40). It was proposed that this positive effect resulted from lactobacilli using GML as a quorum growth stimulant. GML is an analog of the quorum growth stimulant present in many lactobacilli, reutericyclin (10). Our studies have shown that GML and reutericyclin have the same spectrum of antimicrobial activity, both without negative impact on lactobacilli (3, 4).

In this study, we evaluated the effect of GML alone on the growth of L. crispatus in Todd Hewitt broth, and the effect of GML in petrolatum versus GML in PBS on viability of the same lactobacilli (Fig. 5). GML alone in Todd Hewitt broth did not kill L. crispatus at any concentration tested (up to 1,000 µg/mL). The lactobacilli grew to significantly higher 24-h stationary phases at GML concentrations of ≥50 µg/mL, indicating GML was a growth stimulant for this organism (P < 0.0001 for all GML concentrations ≥50 µg/mL). GML in petrolatum and GML in PBS did not result in killing of L. crispatus. No growth was observed in either condition since culture media were not added.

Fig 5.

Line graph showing Log CFUs/mL of Lactobacillus crispatus versus GML concentration. Todd Hewitt broth growth rises near log 9, while GML plus petrolatum and GML plus PBS remain stable near log 7.

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Effect of GML alone in Todd Hewitt and GML + petrolatum versus GML + PBS of viability of Lactobacillus crispatus. Incubation of cultures was stationary at 37°C for 24 h. Means ± standard deviations (SDs) are shown. The black line shows the results of growth of L. crispatus in Todd Hewitt broth from an inoculum of approximately 107 CFU/mL to the value listed after 24-h incubation. Means of growth of L. crispatus in Todd Hewitt at GML concentrations of ≥50 µg/mL were significantly different (Student’s t-test) from means at GML concentrations of 0 and 10 µg/mL (P < 0.0001). The blue line represents L. crispatus in GML + petrolatum. The red line represents L. crispatus in GML + PBS. The means of the blue and red lines at all concentrations of GML were not different.

We also tested GML alone in PBS, petrolatum alone, and GML + petrolatum for effect on growth of one strain each of other skin microbiome organisms, S. capitis and S. epidermidis (Fig. 6). The clinical isolate of S. capitis (41) was overall more susceptible to killing by GML than S. epidermidis, whether treated with GML in petrolatum or in PBS. GML in petrolatum was bactericidal for S. capitis (≥3 log killing) at 0.8 µg/mL, with complete killing at 1.6 µg/mL, compared with 50 µg/mL in PBS, whether bactericidal activity or complete killing was assessed. The normal microbiome S. epidermidis was resistant to killing by GML in petrolatum and in PBS until concentrations of GML of 500 or 1,000 µg/mL, respectively.

Fig 6.

Line graphs show GML kills S. capitis at lower concentrations in petrolatum than PBS, while S. epidermidis shows similar kill curves for both formulations at higher GML doses.

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Effect of GML + petrolatum versus GML + PBS on two strains of coagulase-negative staphylococci (S. capitis and S. epidermidis). Both treatment groups were tested for 24 h at 37°C. Data are log10CFU/mL ± SD (standard deviation).

Effect of GML + petrolatum effect on viridans streptococci

Recently, it has been suggested that skin microbiome viridans streptococci may contribute to AD in very young children (21). Viridans streptococci include at least six subgroups of organisms commonly found in the throat and nose of all people but easily spread to the skin of very young children. We tested one viridans streptococcus from four common subgroups for susceptibility to GML in petrolatum versus GML in PBS (Fig. 7). It is important to emphasize that our experience with streptococci in general is that they do not produce lipases, unlike staphylococci. Consistent with that observation, we observed that all four viridans streptococci were killed by GML in petrolatum at concentrations of 10 µg/mL compared with 50 µg/mL for GML in PBS. Viridans streptococci were approximately 10-fold more susceptible to GML than staphylococci.

Fig 7.

Line graphs show GML dose-response for four Streptococcus strains. Petrolatum formulation achieves bacterial elimination at 10 µg/mL, while PBS formulation requires 50 µg/mL across all four strains.

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Effect of GML + petrolatum versus GML + PBS on four strains of viridans streptococci. Treatment groups were tested for 24 h at 37°C. Data are log10CFU/mL ± standard deviations (SD). Means as determined by Student’s t-test analyses were different between GML + petrolatum (black lines) and GML plus PBS (red lines) at P < 0.00001 for GML concentrations of 5, 10, and 25 µg/mL. Means at GML concentrations of 0, 100, and 500 µg/mL were not different.

DISCUSSION

The goal of this study was to assess whether glycerol monolaurate (GML) added to petrolatum could be used as a mild topical agent to prevent S. aureus and viridans streptococcal colonization of mucous membranes and skin to help in treatment of AD and diabetic ulcers. We showed that six S. aureus strains, both methicillin-resistant and methicillin-sensitive, were killed by GML in petrolatum, where the combination acted with enhanced activity. Importantly, all six S. aureus strains were completely killed by 500 µg/mL, with bactericidal activity (≥3 log reduction in colony-forming units in 24 h) at concentrations of GML of 50 and 100 µg/mL. We showed that GML has the greatest anti-staphylococcal activity compared with other related fatty acid monoesters of glycerol, all of which are generally recognized as safe by the Food and Drug Administration as food additives and for use in cosmetics.

Additionally, we showed that GML acted synergistically with petrolatum, compared with GML alone in PBS, to kill four viridans streptococcal strains. Viridans streptococci have recently been implicated in AD in very young children (21). As expected, GML killed streptococci at 10-fold lower concentrations than required to kill staphylococci. It is likely this difference results from the absence of lipase production by streptococci, compared with lipase production by staphylococci. Lipase production by S. aureus was shown to be the reason for the relatively high amount of GML required to kill the organisms (34). We did not evaluate the ability of GML in petrolatum to kill group A streptococci in the current study. These organisms have not been implicated in driving AD. However, we have previously shown that all group A streptococcal strains are highly susceptible (like viridans streptococci) to GML (3).

We have shown previously in humans that GML at 50,000 µg/mL, dissolved in K-Y Warming Gel, could be used to reduce colonization of the anterior nares by S. aureus and reduce vaginal Candida albicans, while at the same time increasing vaginal lactobacilli (3, 14). GML is soluble in petrolatum at 50,000 µg/mL, so there should be no expected problems with formulation of such a solution. In the prior clinical trial with GML solubilized in K-Y Warming Gel, several women noted transient stinging, presumably due to the non-aqueous K-Y Warming component (14). Women (vaginal) and adults (both male and female anterior nares) treated with GML in K-Y Warming Gel also noted the warming property of the mixture (6, 14). While this was not a problem for the study adult populations, it would potentially be a problem with treatment of the anterior nares of children and treatment of diabetic ulcers. We hypothesize that GML (10,000–50,000 µg/mL) in petrolatum would be a milder treatment.

In the current studies, we evaluated GML in petrolatum for killing four USA200 (CC30; TSST-1 positive), one USA300-like (SE-like X positive), and one USA400 (SEC positive) S. aureus. Previously, we studied possible reasons why skin and soft tissue infections associated with S. aureus are slow to heal. These studies are important both in management of atopic dermatitis and diabetes. The studies suggested that exotoxins, both superantigens and cytotoxins, delay wound healing (42, 43). Indeed, our studies showed that in many cases wounds will not heal at all unless TSST-1, present in the infections, are neutralized (43). Furthermore, the presence of TSST-1 in infection sites leads to more severe infections in atopic dermatitis and diabetes (25, 44, 45).

We also evaluated two coagulase-negative staphylococci for killing by GML in petrolatum, compared with GML in PBS. Some studies suggest that certain coagulase-negative staphylococci contribute to AD and diabetic ulcers (16, 24). Our study found that coagulase-negative strains are also killed by GML at 500 µg/mL, whether in petrolatum or PBS. Incidentally, we tested one additional S. epidermidis strain (data not presented), and this organism was killed completely by GML at 500 µg/mL. These may represent positive effects in AD and diabetic ulcer treatment. However, it could be hoped that normal flora microbes would not be killed. It has previously been shown that GML does not kill normal flora lactobacilli (14, 40). This effect was observed both in vitro (40), and in human studies where women were treated vaginally with 50,000 µg/mL of GML in K-Y Warming Gel (14). There was a 1.5 to 2 log increase in vaginal lactobacilli associated with the treatment (14). This positive effect of retaining normal vaginal lactobacilli likely resulted from those lactobacilli naturally producing an analog of GML called reutericyclin (3, 10). This is supported by both GML and reutericyclin being growth stimulants of lactobacilli, both having a broad and similar spectrum of antimicrobial activity, and both having a similar mechanism of action, that is dissipation of the potential difference across bacterial membranes (3, 10). This also suggests that addition of GML to non-aqueous gels, such as petrolatum and K-Y Warming Gel, would exhibit enhanced bactericidal activity because of disturbance of the membranes by both GML and the non-aqueous gels (3).

We previously showed that GML (50,000 µg/mL) in K-Y Warming Gel could kill S. aureus in a rabbit dermatitis model (39). We observed the same effect by 8 h post-treatment in the current study. Additionally, through in vitro studies, we showed that GML (500 µg/mL) in petrolatum was bactericidal to S. aureus by 1 h post-treatment with complete killing by 2 h.

There are multiple possible explanations for why GML in petrolatum is more antimicrobial than GML alone in PBS. Petrolatum is a complex mixture of lipids, which likely interact with bacterial plasma membranes, possibly increasing GML activity. Petrolatum clearly improves the solubility of GML, and this effect could increase the effective bioavailability of GML. Finally, the hydrophobic nature of petrolatum may promote prolonged contact with bacterial membranes, leading to the increased antimicrobial effect. As we showed previously, the non-aqueous gel, K-Y Warming, functions synergistically to kill bacteria (3). The same possible mechanisms of increased activity were proposed for K-Y Warming increasing activity.

In sum, we have shown that GML in petrolatum could be used, both in vitro and in vivo, to kill pathogenic staphylococci and potentially pathogenic streptococci. This included both methicillin-sensitive and methicillin-resistant S. aureus. Although GML belongs to a large class of fatty acid monoesters, all of which are generally recognized as safe by the FDA as additives to foods and cosmetics, among the group GML has the greatest anti-staphylococcal activity. This may have resulted because the lauric acid side chain in GML exactly spans one-half of the lipid bilayer. We suggest that future studies be done in humans to assess the in vivo efficacy of GML in preventing nasal colonization and topical treatment of AD and diabetic ulcers, the latter of which are notoriously resistant to treatment due to S. aureus colonization.

MATERIALS AND METHODS

Bacteria

S. aureus strains included the following. MN8 is a USA200 (CC30) menstrual toxic shock syndrome isolate (38). The strain is methicillin-sensitive, like most USA200 (CC30) strains, produces the superantigen TSST-1 and has a mutation in the α-cytotoxin gene, reducing the cytotoxin production by 50-fold (46). MNPE is a USA200 (CC30) menstrual TSS isolate from a fatal case of post-influenza hemorrhagic pneumonia (47). The strain is methicillin-sensitive, produces the superantigen TSST-1, and produces wild-type amounts of the cytotoxin α-toxin (hla; lacks the mutation that reduces the amount of the cytotoxin in >95% of menstrual TSS isolates). MNWH is a USA200 (CC30) menstrual TSS isolate from a recurrent case (48). The isolate is methicillin-resistant (has a hospital-associated SCCmec DNA element), produces TSST-1, and has the hla mutation, reducing the amount of the cytotoxin by 50-fold (48). Unusually, the MNWH strain lacks carotenoid pigment production that typifies S. aureus. Strain FRI1169 was originally obtained from Dr. Merlin Bergdoll (now deceased) from the University of Wisconsin Food Research Institute. This isolate was from a patient with menstrual TSS (49). The organism is USA200 (CC30), produces TSST-1, produces only low levels on α-toxin, and is methicillin-sensitive. MNKN is a USA400 (CC1) community-associated methicillin-resistant isolate from a fatal case of hemorrhagic pneumonia (50). The strain produces the superantigen staphylococcal enterotoxin C (SEC) and produces wild-type amounts of the cytotoxin α-toxin (50). HP1 is a recent clone of S. aureus from a patient with atopic dermatitis, and which is characterized by its hyper-pink growth on mannitol salt agar (30). The organism is related to USA300 (CC8), is methicillin-sensitive, and produces both SE-like X and wild-type α-toxin (30).

Strains of coagulase-negative staphylococci included a recent clinical isolate of S. capitis (41) and a normal microbiome culture of S. epidermidis. All organisms in this study are low passage and are maintained as −80°C frozen stocks in the Schlievert laboratory.

A Lactobacillus crispatus strain and four strains of viridans streptococci are maintained as −80°C frozen stocks in the Schlievert laboratory. The viridans streptococci included Streptococcus intermedius, Streptococcus gordonii, Streptococccus sanguinis, and Streptococcus salivarius.

Fatty acid monoesters of glycerol

Glycerol monolaurate (GML) was purchased from Colonial Chemical Company, South Pittsburg, TN. The remaining compounds (glycerol monocaprate, glycerol monocaprylate, and glycerol monomyristate) were purchased from Sigma-Aldrich, St. Louis, MO. All compounds were solubilized in 100% ethanol at 100,000 µg/mL as stock solutions.

In vitro experiments

All organisms for testing were first cultured overnight at 37°C with 200 rpm shaking in Todd Hewitt broth (Difco Laboratories, Detroit, MI) for staphylococci and stationary for lactobacilli and streptococci. Subsequently the appropriate dilutions were made in Todd Hewitt broth for inoculums of approximately 106/mL or 107/mL into Todd Hewitt broth, phosphate-buffered saline (0.005 M sodium phosphate, pH 7.2; 0.15M NaCl), or petrolatum (generic over-the-counter brand purchased from Walgreen’s Pharmacy).

In the first set of experiments, various glycerol monoesters (50 µL volumes in ethanol) individually were added to 25 mL volumes of Todd Hewitt broth in 125-mL Erlenmeyer flasks, with the corresponding control flasks having the same volumes of ethanol alone. Subsequently, 107/mL of S. aureus MN8 were added to each flask. The flasks were then shaken (200 rpm) at 37°C for 24 h. Plate counts were then performed to determine CFUs/mL. It is important to note that glycerol monoesters at concentrations above 100 µg/mL in aqueous solutions are insoluble. However, the antimicrobial activity of these esters is increased above the solubility limit. This indicates that the monoesters likely embed into bacterial membranes, with more monoester becoming soluble, and the embedding process continuing until the bacteria die.

Petrolatum is a semi-solid at 37°C, and thus the compound was melted at 65°C and 2 mL added to sterile glass tubes. Then, the various tested concentrations of GML, PBS, or 100% ethanol (as control) in 20 µL volumes were added. Finally, the individual staphylococci were added to each tube in 20 µL volumes, and immediately the tubes were mixed and cooled to 37°C to prevent heat killing of the staphylococci, lactobacilli, and streptococci. The tubes were incubated for designated time periods, and plate counts were used to assess CFUs/mL.

Because GML in petrolatum and petrolatum alone are semi-solid are 37°C, we determined CFUs/mL by immersing sterile cotton swabs in the gels and plating directly with one swab onto sheep blood agar plates and then immersing a second swab into 0.9 mL of Todd Hewitt broth for additional serial dilutions in Todd Hewitt broths. Our past experience is that the swabs take up approximately 0.1 mL of volumes. Thus, the lowest dilution plated was the 10−1 dilution for a lower limit of detection of 10 CFUs/mL.

Rabbit studies

Four New Zealand white rabbits (2–3 kg), both sexes, were used in these studies. The studies were performed with ABSL-2 conditions under an approved protocol by the University of Iowa IACUC (Number 3072547-001). Rabbits were administered buprenorphine for pain management by a University of Iowa veterinary technician. Then, the animals had both flanks shaved. The animals subsequently received approximately 109 CFUs of S. aureus strain MN8 in 0.1 mL of PBS, painted onto the exposed skin over a 2 × 2 cm area. Then, the same areas were painted one-time with 0.5 mL of GML (50,000 µg/mL) in petrolatum or petrolatum alone. The animals were then returned to their cages and monitored for viable S. aureus at 8 h. For plate count determinations, the rabbits were swabbed diagonally across the infected area of exposed skin by rolling a PBS-wetted swab (holds 0.1 mL) one time. At 8 h, the veterinary technician euthanized the animals. Plate counts were performed on sheep blood agar plates after making dilutions in Todd Hewitt broths followed by immediate plating. Previously in similar experiments, we observed no toxicity to the rabbits of GML (39). Similar to that prior study, the animals remained healthy in appearance, had no unusual swelling or reddening of the flank application sites.

Statistics

Data in graphs were presented as means ± standard deviations. Student’s t-test analysis was used to assess differences in mean values. All in vitro experiments were performed at least two times. The rabbit studies were performed one time only with S. aureus since our prior studies with GML in K-Y Warming Gel, and a more recent study with a compound related to GML, both showed killing of S. aureus (39, 51).

ACKNOWLEDGMENTS

This research was funded by National Institutes of Health Grant U19 AI117673 and 1UM1AI151958 (to Atopic Dermatitis Research Network investigators).

Contributor Information

Patrick M. Schlievert, Email: Patrick-Schlievert@uiowa.edu.

Ryan S. Doster, University of Louisville, Louisville, Kentucky, USA

DATA AVAILABILITY

Data and strains used in these studies are available upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data and strains used in these studies are available upon request.

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