Publications by authors named "Lisa Mullins"

12 Publications

  • Page 1 of 1

Combinations of peptides synergistically activate the regenerative capacity of skin cells in vitro.

Int J Cosmet Sci 2021 Jul 17. Epub 2021 Jul 17.

The Procter & Gamble Company, Cincinnati, Ohio, USA.

Objective: To explore synergistic effects related to skin regeneration, peptides with distinct biological mechanisms of action were evaluated in combination with different skin cell lines in the presence or absence of niacinamide (Nam). Furthermore, the synergistic responses of peptide combinations on global gene expression were compared with the changes that occur with fractional laser resurfacing treatment, a gold standard approach for skin rejuvenation, to further define optimal peptide combinations.

Methods: Microarray profiling was used to characterize the biological responses of peptide combinations (+/- Nam) relative to the individual components in epidermal keratinocyte and dermal fibroblast cell lines. Cellular functional assays were utilized to confirm the synergistic effects of peptide combinations. Bioinformatics approaches were used to link the synergistic effects of peptide combinations on gene expression to the transcriptomics of the skin rejuvenation response from fractional laser treatment.

Results: Microarray analysis of skin cells treated with peptide combinations revealed synergistic changes in gene expression compared with individual peptide controls. Bioinformatic analysis of synergy genes in keratinocytes revealed the activation of NRF2-mediated oxidative stress responses by a combination of Ac-PPYL, Pal-KTTKS and Nam. Additional analysis revealed direct downstream transcriptional targets of NRF2/ARE exhibiting synergistic regulation by this combination of materials, which was corroborated by a cellular reporter assay. NRF2-mediated oxidative stress response pathways were also found to be activated in the transcriptomics of the early skin rejuvenation response to fractional laser treatment, suggesting the importance of this biology in the early stages of tissue repair. Additionally, the second combination of peptides (pal-KT and Ac-PPYL) was found to synergistically restore cellular ATP levels that had been depleted due to the presence of ROS, indicating an additional mechanism, whereby peptide synergies may accelerate skin repair.

Conclusion: Through combinatorial synergy studies, we have identified additional in vitro skin repair mechanisms beyond the previously described functions of individual peptides and correlated these to the transcriptomics of the skin rejuvenation response of fractional laser treatment. These findings suggest that specific peptides can act together, via complementary and synergistic mechanisms, to holistically enhance the regenerative capacity of in vitro skin cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ics.12725DOI Listing
July 2021

Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age.

J Am Acad Dermatol 2018 Jan 14;78(1):29-39.e7. Epub 2017 Nov 14.

The Procter & Gamble Company, Cincinnati, Ohio.

Background: Intrinsic and extrinsic factors, including ultraviolet irradiation, lead to visible signs of skin aging.

Objective: We evaluated molecular changes occurring in photoexposed and photoprotected skin of white women 20 to 74 years of age, some of whom appeared substantially younger than their chronologic age.

Methods: Histologic and transcriptomics profiling were conducted on skin biopsy samples of photoexposed (face and dorsal forearm) or photoprotected (buttocks) body sites from 158 women. 23andMe genotyping determined genetic ancestry.

Results: Gene expression and ontologic analysis revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, senescence, and epidermal barrier; these changes were accelerated in the 60s and 70s. The gene expression patterns from the subset of women who were younger-appearing were similar to those in women who were actually younger.

Limitations: Broader application of these findings (eg, across races and Fitzpatrick skin types) will require further studies.

Conclusions: This study demonstrates a wide range of molecular processes in skin affected by aging, providing relevant targets for improving the condition of aging skin at different life stages and defining a molecular pattern of epidermal gene expression in women who appear younger than their chronologic age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2017.09.012DOI Listing
January 2018

LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens.

mBio 2014 Sep 30;5(5):e01551-14. Epub 2014 Sep 30.

Discovery Biology, Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA.

Unlabelled: The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor.

Importance: New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01551-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196226PMC
September 2014

Susceptibility to antimicrobial agents among bovine mastitis pathogens isolated from North American dairy cattle, 2002-2010.

J Vet Diagn Invest 2013 Sep 1;25(5):581-91. Epub 2013 Aug 1.

1Cynthia J. Lindeman, Zoetis Inc., 333 Portage Street, Kalamazoo, MI 49007.

Approximately 8,000 isolates of Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Staphylococcus aureus, and Escherichia coli, isolated by 25 veterinary laboratories across North America between 2002 and 2010, were tested for in vitro susceptibility to beta-lactam, macrolide, and lincosamide drugs. The minimal inhibitory concentrations (MICs) of the beta-lactam drugs remained low against most of the Gram-positive strains tested, and no substantial changes in the MIC distributions were seen over time. Of the beta-lactam antimicrobial agents tested, only ceftiofur showed good in vitro activity against E. coli. The MICs of the macrolides and lincosamides also remained low against Gram-positive mastitis pathogens. While the MIC values given by 50% of isolates (MIC50) for erythromycin and pirlimycin and the streptococci were all low (≤0.5 µg/ml), the MIC values given by 90% of isolates (MIC90) were higher and more variable, but with no apparent increase over time. Staphylococcus aureus showed little change in erythromycin susceptibility over time, but there may be a small, numerical increase in pirlimycin MIC50 and MIC90 values. Overall, the results suggest that mastitis pathogens in the United States and Canada have not shown any substantial changes in the in vitro susceptibility to beta-lactam, macrolide, and lincosamide drugs tested over the 9 years of the study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1040638713498085DOI Listing
September 2013

Pyridone-conjugated monobactam antibiotics with gram-negative activity.

J Med Chem 2013 Jul 27;56(13):5541-52. Epub 2013 Jun 27.

Worldwide Medicinal Chemistry, ‡Computational Chemistry, §Antibacterials Research Unit, ∥Pharmacokinetics, Dynamics & Metabolism, ⊥Structural Biology, Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm400560zDOI Listing
July 2013

Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents.

Bioorg Med Chem Lett 2012 Nov 24;22(22):6832-8. Epub 2012 Sep 24.

Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340, USA.

The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.09.058DOI Listing
November 2012

Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections.

Bioorg Med Chem Lett 2012 Sep 20;22(18):5989-94. Epub 2012 Jul 20.

Medicinal Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.07.005DOI Listing
September 2012

Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections.

J Med Chem 2012 Feb 8;55(4):1662-70. Epub 2012 Feb 8.

Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, United States.

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm2014875DOI Listing
February 2012

Potent inhibitors of LpxC for the treatment of Gram-negative infections.

J Med Chem 2012 Jan 11;55(2):914-23. Epub 2012 Jan 11.

Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm2014748DOI Listing
January 2012

Preparation, gram-negative antibacterial activity, and hydrolytic stability of novel siderophore-conjugated monocarbam diols.

ACS Med Chem Lett 2011 May 2;2(5):385-90. Epub 2011 Mar 2.

Thomas Gootz Consulting, LLC, Estes Park, Colorado 80517, United States.

A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ml200012fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018130PMC
May 2011

5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV.

Bioorg Med Chem Lett 2009 Sep 3;19(18):5302-6. Epub 2009 Aug 3.

Pfizer Global Research and Development, 445 Eastern Point Rd., Groton, CT 06340, United States.

Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2009.07.141DOI Listing
September 2009

Understanding metabolic pathways for skin anti-aging.

J Drugs Dermatol 2009 Jul;8(7 Suppl):s4-7

P&G Beauty & Grooming, The Procter & Gamble Company, Miami Valley Innovation Center, Cincinnati, Ohio 45253, USA.

Global gene expression profiling provides a useful means to identify key aspects of the skin aging process, and provides information to help develop new skin technologies. Important aspects of skin aging that can be addressed include skin hydration, barrier, matrix, pigmentation and antioxidant capacity. Human skin equivalent cultures allow topical application of test compounds, combinations and products to their stratum corneum surface and measurement of predictive biomarkers. Using this in vitro biomarker approach, it is possible to detect skin barrier enhancement in response to the compounds niacinamide and hexamidine, matrix effects to the peptides Pal-KT and Pal-KTTKS, and hydration and matrix responses to niacinamide and N-acetylglucosamine.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2009
-->