5-Dodecanolide interferes with biofilm formation and reduces the virulence of Methicillin-resistant Staphylococcus aureus (MRSA) through up regulation of agr system

Alaguvel Valliammai,James Prabhanand Bhaskar,Sivasamy Sethupathy,Anthonymuthu Selvaraj,Arumugam Priya,Venkateswaran Krishnan,Shunmugiah Karutha Pandian

doi:10.1038/s41598-019-50207-y

Alaguvel Valliammai, James Prabhanand Bhaskar + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-50207-y

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Abstract

Methicillin resistant Staphylococcus aureus (MRSA) is a predominant human pathogen with high morbidity that is listed in the WHO high priority pathogen list. Being a primary cause of persistent human infections, biofilm forming ability of S. aureus plays a pivotal role in the development of antibiotic resistance. Hence, targeting biofilm is an alternative strategy to fight bacterial infections. The present study for the first time demonstrates the non-antibacterial biofilm inhibitory efficacy of 5-Dodecanolide (DD) against ATCC strain and clinical isolates of S. aureus. In addition, DD is able to inhibit adherence of MRSA on human plasma coated Titanium surface. Further, treatment with DD significantly reduced the eDNA synthesis, autoaggregation, staphyloxanthin biosynthesis and ring biofilm formation. Reduction in staphyloxanthin in turn increased the susceptibility of MRSA to healthy human blood and H2O2 exposure. Quantitative PCR analysis revealed the induced expression of agrA and agrC upon DD treatment. This resulted down regulation of genes involved in biofilm formation such as fnbA and fnbB and up regulation of RNAIII, hld, psmα and genes involved in biofilm matrix degradation such as aur and nuc. Inefficacy of DD on the biofilm formation of agr mutant further validated the agr mediated antibiofilm potential of DD. Notably, DD was efficient in reducing the in vivo colonization of MRSA in Caenorhabditis elegans. Results of gene expression studies and physiological assays unveiled the agr mediated antibiofilm efficacy of DD.

Highlights

Staphylococcus aureus is an important human pathogen, which plays a remarkable role in an array of infections from negligible skin infections to life concerning invasive illness such as bacteremia, infective endocarditis etc[1]
DD treatment was administered in the range of 50–500 μg/mL. 200 μg/mL and 350 μg/mL were determined as Biofilm inhibitory concentration (BIC) for methicillin susceptible S. aureus (MSSA) A8 and MSSA 46, MSSA 51, Methicillin resistant Staphylococcus aureus (MRSA) 395, MRSA 410 and MRSA 44 respectively (Fig. 2b)
Inhibition of biofilm formation will prevent the progression of infection and sensitize the bacterial cells towards host immune clearance and antibacterial therapy as well

Summary

Introduction

Staphylococcus aureus is an important human pathogen, which plays a remarkable role in an array of infections from negligible skin infections to life concerning invasive illness such as bacteremia, infective endocarditis etc[1]. Protein components of the bacterial cell wall facilitate the adhesion of S. aureus to the abiotic surfaces thereby establish persistent infections through biofilm formation. The secreted extracellular polymeric substances extracellular DNA (eDNA), extracellular proteins, lipids, amyloid fibrils and polysaccharides such as polysaccharide intracellular adhesin (PIA) provide firm organization to the biofilm matrix. These biomolecules get absorbed on the implant surface providing initial attachment to the bacterial cell for the establishment of biofilm[3,4]. Ica independent biofilm formation has been described in MRSA and it is primarily mediated by the production of eDNA and cell surface adhesion proteins[8,9]. Complementing antibiotics or synthetic antibiofilm agents with natural compounds will progress the therapy for persistent bacterial infections

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