Discovery of Antivirulence Agents against Methicillin-Resistant Staphylococcus aureus

Khodaverdian, Varandt Y.; Pesho, Michelle; Truitt, Barbara; Bollinger, Lucy B.; Patel, Parita; Nithianantham, Stanley; Yu, Guan‐Ping; Delaney, Elizabeth; Jankowsky, Eckhard; Shoham, Menachem

doi:10.1128/aac.00269-13

Cited by 122 publications

(99 citation statements)

References 30 publications

(35 reference statements)

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“…16 The data show that half of patients with pneumonia and sepsis were infected with MRSA. 17 Pneumonia and sepsis are life-threatening diseases with high mortality rates (60% and 63.6%, respectively).…”

Section: Discussionmentioning

confidence: 99%

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

Sun¹,

Wei²,

Liu³

et al. 2015

IJN

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The Gram-positive bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA) can cause infections in the bloodstream, endocardial tissue, respiratory tract, culture-confirmed skin, or soft tissue. There are currently no effective vaccines, and none are expected to become available in the near future. An effective vaccine capable of eliciting both systemic and mucosal immune responses is also urgently needed. Here, we reported a novel oil-in-water nanoemulsion adjuvant vaccine containing an MRSA recombination protein antigen, Cremophor EL-35 ® as a surfactant, and propylene glycol as a co-surfactant. This nanoemulsion vaccine, whose average diameter was 31.34±0.49 nm, demonstrated good protein structure integrity, protein specificity, and good stability at room temperature for 1 year. The intramuscular systemic and nasal mucosal immune responses demonstrated that this nanoemulsion vaccine could improve the specific immune responses of immunoglobulin (Ig)G and related subclasses, such as IgG1, IgG2a, and IgG2b, as well as IgA, in the serum after Balb/c mice intramuscular immunization and C57 mice nasal immunization. Furthermore, this nanoemulsion vaccine also markedly enhanced the interferon-γ and interleukin-17A cytokine cell immune response, improved the survival ratio, and reduced bacterial colonization. Taken together, our results show that this novel nanoemulsion vaccine has great potential and is a robust generator of an effective intramuscular systemic and nasal mucosal immune response without the need for an additional adjuvant. Thus, the present study serves as a sound scientific foundation for future strategies in the development of this novel nanoemulsion adjuvant vaccine to enhance both the intramuscular systemic and nasal mucosal immune responses.

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Section: Discussionmentioning

confidence: 99%

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

Sun¹,

Wei²,

Liu³

et al. 2015

IJN

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“…In an in silico screen, diflunisal was predicted to inhibit AgrC-mediated phosphorylation of AgrA. Consistent with this prediction, diflunisal treatment inhibited rabbit red blood cell lysis and significantly lowered transcript levels of hla, RNAIII, and psm␣ without affecting bacterial growth (7,11). However, the efficacy of diflunisal in mitigating staphylococcal virulence in vivo has yet to be determined.…”

mentioning

confidence: 86%

“…In silico analyses identified the NSAID diflunisal as a potent inhibitor of AgrA-mediated gene expression (11). We previously demonstrated that Agr-dependent virulence factor production, and in particular synthesis of alpha-type PSMs, significantly contributes to skeletal cell death and bone destruction associated with S. aureus osteomyelitis (5,14,18).…”

Section: Diflunisal Inhibits S Aureus Cytotoxicity Toward Human and mentioning

confidence: 99%

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Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis

Hendrix

Spoonmore

Wilde

et al. 2016

Antimicrob Agents Chemother

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dStaphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro. Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo. Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis. Osteomyelitis is an invasive infection of bone, most frequently caused by the Gram-positive pathogen Staphylococcus aureus (1). Treatment of osteomyelitis is confounded by an increasing prevalence of antimicrobial resistance, as well as the propensity for patients to develop pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. For this reason, patients suffering from osteomyelitis often undergo multiple surgical debridements to remove infected and necrotic bone, while also receiving prolonged antimicrobial therapy (1, 2). Despite these aggressive measures, a subset of patients with acute osteomyelitis will progress to chronic infection, which is highly refractory to further intervention and may require months to years of antimicrobial treatment. Moreover, although adult osteomyelitis is often secondary to comorbidities such as trauma, surgery, diabetes, or vascular insufficiency, hematogenous osteomyelitis in previously healthy children is more prevalent in the current era of community-acquired staphylococcal infections (3). Children are inherently vulnerable to adverse outcomes during osteomyelitis given the presence of active epiphyseal plates and thus have the potential to develop limb-length discrepancy (4). Taken together, these facts illustrate the need for adjunctive therapies that lessen the morbidity ...

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“…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).…”

mentioning

confidence: 99%

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

Kuo

Hoch

et al. 2015

Antimicrob Agents Chemother

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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...

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Discovery of Antivirulence Agents against Methicillin-Resistant Staphylococcus aureus

Cited by 122 publications

References 30 publications

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis

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

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