Novel Quorum-Quenching Agents Promote Methicillin-Resistant Staphylococcus aureus (MRSA) Wound Healing and Sensitize MRSA to β-Lactam Antibiotics

Abstract

The dwindling repertoire of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) calls for novel treatment options. Quorum-quenching agents offer an alternative or an adjuvant to antibiotic therapy. Three biaryl hydroxyketone compounds discovered previously (F1, F12, and F19; G. Yu, D. Kuo, M. Shoham, and R. Viswanathan, ACS Comb Sci 16:85-91, 2014) were tested for efficacy in MRSA-infected animal models. Topical therapy of compounds F1 and F12 in a MRSA murine wound infection model promotes wound healing compared to the untreated control. Compounds F1, F12, and F19 afford significant survival benefits in a MRSA insect larva model. Combination therapy of these quorum-quenching agents with cephalothin or nafcillin, antibiotics to which MRSA is resistant in monotherapy, revealed additional survival benefits. The quorum-quenching agents sensitize MRSA to the antibiotic by a synergistic mode of action that also is observed in vitro. An adjuvant of 1 g/ml F1, F12, or F19 reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those for vancomycin, the antibiotic often prescribed for MRSA infections. These findings suggest that it is possible to resurrect obsolete antibiotic therapies in combination with these novel quorum-quenching agents. Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread bacterial pathogen, causing various infections, ranging from skin and soft tissue infections to serious invasive infections, such as pneumonia, endocarditis, bacteremia, and sepsis (1, 2). Rising antibiotic resistance and diminishing investment by the pharmaceutical industry in the development of new antibiotics have created an urgent need for novel anti-MRSA agents (3). Quorum-quenching agents provide an alternative and an adjuvant to conventional antibiotic therapy (4, 5). The mechanism of action of quorum-quenching agents is fundamentally different from that for antibiotics. Quorum-quenching agents are neither bactericidal nor bacteriostatic. They inhibit the production of disease-causing toxins by the pathogen, thereby disarming the pathogen of its capacity to inactivate host defense factors. An intact host immune system has a better chance to clear a bacterial infection. A quorum-quenching agent tips the balance of bacterial virulence factors and host defense factors in favor of the host.Virulence factor production in Staphylococcus aureus is regulated by a quorum-sensing mechanism predominantly under the control of the agr operon (6, 7). In previous work, we have identified small-molecule biaryl hydroxyketone compounds that target the response regulator AgrA and inhibit its interaction with promoter P3, curtailing the production of toxins and virulence factors (8). In a follow-up study, a combinatorial library of 148 compounds was synthesized based on the most efficacious hit compound (9). A member of this biaryl hydroxyketone library, named F12, was the most efficacious of the synthesized compounds, demonstrating 98% in vitro MRSA rabbit erythrocyte hemolysis inhi...

Enhanced antibacterial activity of silica nanorattles with ZnO combination nanoparticles against methicillin-resistant Staphylococcus aureus

“…During past few decades, MRSA has attracted increasing public attention across the world for its ability to cause a wide range of infections, ranging from localized skin diseases to lifethreatening pneumonia and sepsis [2][3][4]41]. Approximately 18,000 deaths have been recorded due to MRSA infections each year, and the cost associated with MRSA skin and soft tissue infections alone ranges from 108 to 343 million dollars annually in the United States [42,43]. Even though new types of antibiotics have been explored and applied in recent years, the emergence of resistant S. aureus strains has dramatically increased.…”

“…Nanomaterials, as novel and effective agents to inhibit, reduce or even kill numerous microorganisms, have been extensively applied in biomedical fields [1][2][3][4]. Some nanoparticles, such as zinc oxide, silver, copper and iron oxide nanoparticles, have been successfully introduced in anti-infecting agents applied in wound dressings [5,6], protective clothing [7], nanomedicines, water treatment [8], food preservation and disinfecting agents [9][10][11][12]. ZnO nanoparticles are among the most heavily researched antibacterial materials due to their broad spectrum antibacterial properties, variety of preparation methods, easy modification of physico-chemical properties, and their low toxicity.…”

Advances in Microbiology, Infectious Diseases and Public Health

“…Screening natural QSIs using more than five hundred marine bacterial strains identified six novel cyclodepsipeptides from the marine Gramnegative bacterium Photobacterium, solonamide A/B and ngercheumicins (F, G, H, and I), as agr QS inhibitors (Mansson et al 2011;Kjaerulff et al 2013). An adjuvant of 1 μg ml À1 three biaryl hydroxyketones (F1, F12, or F19) reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those of vancomycin in murine models (Kuo et al 2015). In another study, a cyclic peptide (Avellanin C) obtained from the fungus Hamigera ingelheimensis attenuated the QS system of the S. aureus agr reporter strain (8325-4) with an IC 50 value of 4.4 μM .…”

Novel roles of staphylococcal proteases and cross talk in biofilm formation and virulence

“…One major virulence regulator is the agr quorum-sensing system, which positively regulates secreted proteases and numerous other virulence factors of the staphylococci [22,23]. Because S. aureus agr mutants are attenuated in certain infection types [24][25][26], the inhibition of S. aureus quorum sensing (quorum quenching) is a desirable area of research as a therapeutic for S. aureus infections that are otherwise difficult to eradicate [27][28][29]. My recent work has characterized a novel quorum quencher produced by the animal-associated staphylococcal species S. caprae.…”

“…Additionally, quorum quenchers can be used in tandem with antibiotics for a synergistic effect in vivo [361]. Previous work has shown that quorum quenchers increase S. aureus sensitivity to antibiotics [28,362]. Another appealing aspect of quorum quenchers is that S. aureus does not appear to develop resistance to them in vitro [170,363].…”