Antivirulence Agent as an Adjuvant of β-Lactam Antibiotics in Treating Staphylococcal Infections

Abstract

Staphylococcus aureus can cause a plethora of life-threatening infections. Antibiotics have been extensively used to treat S. aureus infections. However, when antibiotics are used at sub-inhibitory concentrations, especially for β-lactam antibiotics, they may enhance staphylococcal pathogenicity and exacerbate the infection. The combination of antivirulence agents and antibiotics may be a novel approach to controlling antibiotic-induced S. aureus pathogenicity. We have illustrated that under in vitro conditions, antivirulence agent M21, when administered concurrently with ampicillin, suppressed the expression and production of virulence factors induced by ampicillin. In a mouse peritonitis model, M21 reduced bacterial load irrespective of administration of ampicillin. In a bacteremia model, combinatorial treatment consisting of ampicillin or ceftazidime and M21 increased the survival rate of mice and reduced cytokine abundance, suggesting the suppression of antibiotic-induced virulence by M21. Different from traditional antibiotic adjuvants, an antivirulence agent may not synergistically inhibit bacterial growth in vitro, but effectively benefit the host in vivo. Collectively, our findings from this study demonstrated the benefits of antivirulence–antibiotic combinatorial treatment against S. aureus infections and provide a new perspective on the development of antibiotic adjuvants.

The Cell Wall, Cell Membrane and Virulence Factors of Staphylococcus aureus and Their Role in Antibiotic Resistance

“…Finding adjuvants to antibiotic therapy is promising because they can allow treatment of infections from resistant strains with antibiotics that are already in practice. Studies reporting the potential of anti-virulence strategies as adjuvants to antibiotics against S aureus have increased in the past decade [ 81 , 82 , 83 , 84 ]. There are many advantages of using anti-virulence adjuvants.…”

Bi-doped ZnAl-layered double hydroxides with enhanced photocatalytic activity for ciprofloxacin degradation: the synergistic effect of Bi doping and oxygen vacancies

“…1,2 CIP exhibits strong antibacterial activity against both Gram-negative and Gram-positive bacteria and has been widely used in the field of human and animal infectious diseases and viruses. [3][4][5] However, CIP is usually not fully metabolized in the body of humans and animals, and mostly, CIP is excreted into the environment in a pharmacologically active form through urine and feces. In addition, CIP is also present in hospital and pharmaceutical wastewater.…”

Synergistic Augmentation of Beta-Lactams: Exploring Quinoline-Derived Amphipathic Small Molecules as Antimicrobial Potentiators against Methicillin-Resistant Staphylococcus aureus

“…Recent literature suggests that the prime focus on membrane-perturbing antibiotic adjuvant design and application has been placed on Gram-negative priority pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli compared to Gram-positive candidates like MRSA . Although an array of SMs like brominated carbazoles, 1,4-napthoquinone, engineered antivirulence agents, and phytochemicals have been tested as antibiotic adjuvants for their synergistic antibacterial effect against MRSA, − there is a significant research gap in the development of antibiotic membrane perturbers against the organism, and Gram-positive pathogens as a whole. In addition, the application of weak membrane perturbers in the accentuation of antibiotic efficacy has been successfully reported in recent literature against Gram-negative superbugs and the strategy has been underutilized in Gram-positive bacteria.…”