Increased resistance of a methicillin-resistant Staphylococcus aureus \u0394agr mutant with modified control in fatty acid metabolism

Hun-Suk Song,Shashi Kant Bhatia,Yeong-Hoon Han,Yun-Gon Kim,Tae-Rim Choi,Yung-Hun Yang,Jun Young Park,Ranjit Gurav,Soo-Yeon Yang,Ye-Lim Park,Jae-Seok Kim,Hwang-Soo Joo

doi:10.1186/s13568-020-01000-y

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) strains are distinct from general Staphylococcus strains with respect to the composition of the membrane, ability to form a thicker biofilm, and, importantly, ability to modify the target of antibiotics to evade their activity. The agr gene is an accessory global regulator of gram-positive bacteria that governs virulence or resistant mechanisms and therefore an important target for the control of resistant strains. However, the mechanism by which agr impacts resistance to β-lactam antibiotics remains unclear. In the present study, we found the Δagr mutant strain having higher resistance to high concentrations of β-lactam antibiotics such as oxacillin and ampicillin. To determine the influence of variation in the microenvironment of cells between the parental and mutant strains, fatty acid analysis of the supernatant, total lipids, and phospholipid fatty acids were compared. The Δagr mutant strain tended to produce fewer fatty acids and retained lower amounts of C16, C18 fatty acids in the supernatant. Phospholipid analysis showed a dramatic increase in the hydrophobic longer-chain fatty acids in the membrane. To target membrane, we applied several surfactants and found that sorbitan monolaurate (Span20) had a synergistic effect with oxacillin by decreasing biofilm formation and growth. These findings indicate that agr deletion allows for MRSA to resist antibiotics via several changes including constant expression of mecA, fatty acid metabolism, and biofilm thickening.

Highlights

Staphylococcus aureus is a successful indigenous pathogen in humans, which expresses a wide range of virulence factors, including toxins, immune evasive surface factors, and virulent enzymes (Turner et al 2019)
methicillin-resistant S. aureus (MRSA) strains are generally classified into healthcare-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA), which differ with respect to several
To understand the nature of these differences, we further explored the differences in fatty acid distribution and membrane fatty acid composition between the wild-type (WT) and agr mutant strains to determine their influence on antibiotic resistance

Summary

Introduction

Staphylococcus aureus is a successful indigenous pathogen in humans, which expresses a wide range of virulence factors, including toxins, immune evasive surface factors, and virulent enzymes (Turner et al 2019). Multi-resistant methicillin-resistant S. aureus (MRSA) has emerged as a major threat to human health. The antibiotic resistance of MRSA poses a significant treatment challenge and gaining greater insight into the mechanisms contributing to this resistance can help to guide treatment and control strategies. In MRSA, the main function of Agr is to regulate biofilm formation and toxin production (Rutherford and Bassler 2012). The agr operon acquires signal molecules via a positively regulated mechanism so that RNAII (agrACDB) activates the production of phenol soluble modulins (PSMs) and the RNAIII transcripts are activated to produce δ-hemolysin; the RNAIII transcript itself controls capsule formation, toxin production, and central metabolism of the strain (Kong et al 2016)

Methods

Results

Conclusion