Low-Molecular-Weight Branched Polyethylenimine Potentiates Ampicillin against MRSA Biofilms

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a serious threat worldwide. MRSA is the predominant species isolated from medical-device-related biofilm infections and chronic wounds. Its ability to form biofilms grants it resistance to almost all antibiotics on the market. Answering the call for alternative treatments, our lab has been investigating the efficacy of 600 Da branched polyethylenimine (BPEI) as a β-lactam potentiator against bacterial biofilms. Our previous study showed promise against methicillin-resistant Staphylococcus epidermidis biofilms. This study extends our previous findings to eradicate a more virulent pathogen: MRSA biofilms. Microtiter minimum biofilm eradication concentration models, crystal violet assays, and electron microscopy images show synergistic effects between BPEI and ampicillin as a two-step mechanism: step one is the removal of the extracellular polymeric substances (EPS) to expose individual bacteria targets, and step two involves electrostatic interaction of BPEI with anionic teichoic acid in the cell wall to potentiate the antibiotic.

PEGylation of Polyethylenimine Lowers Acute Toxicity while Retaining Anti-Biofilm and β-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens

“…Bacterial cells that remain after cleansing survive antibiotic therapy, quickly populate the wound bed, and regenerate the biofilm matrix. An advantage of 600 Da BPEI is its ability to disrupt biofilms of staphylococci 12 , 13 , 48 and P. aeruginosa . 4 PEGylated 600 Da BPEI retains these anti-biofilm properties and is a superior anti-biofilm agent compared to non-PEGylated 600 Da BPEI.…”

Eradication of Biofilm-Mediated Methicillin-Resistant Staphylococcus aureus Infections In Vitro : Bacteriophage-Antibiotic Combination

“…Methicillin-resistant Staphylococcus aureus (MRSA) is the leading species isolated from biofilm-associated infections such as chronic wounds and medical devices. The aggregation of microorganisms inside the protective structure of exopolysaccharides leads to increased bacterial fitness and survival rate due to altered metabolic activity of the biofilm communities, low diffusion of antibiotics inside the biofilm matrix, and blockage of the exposure to immune cells/antibodies ( 1 – 4 ). The narrow pipeline of antibiotics and the development of resistance even to last-resort antibiotics raises the urgent demand for novel antibacterial interventions ( 5 – 8 ).…”

Dual-Function Potentiation by PEG-BPEI Restores Activity of Carbapenems and Penicillins against Carbapenem-Resistant Enterobacteriaceae

“…These effects do not require β-lactamase inhibitors (BLIs) and likely occur by sequestering Zn 2+ ions essential for NDM-1. The importance of using low molecular weight BPEI potentiators against CRE E. coli and K. pneumoniae is magnified by the ability of 600 Da BPEI to disrupt biofilms and resistance in P. aeruginosa and staphylococci. − We previously identified potentiation mechanisms across different antibiotic classes by lowering lipopolysaccharide (LPS) barriers, inhibiting cell wall synthesis, and disrupting biofilms. ,, The antibiofilm properties of 600 Da BPEI is associated with biofilm formation inhibition and an extracellular polymeric substance (EPS)-disruption mechanism. , This current work expands not only the potential utility of these potentiators against infectious pathogens but also our understanding of the multifunction nature of these compounds.…”

“…Thus, we envision PEG-BPEIs as topical agents applied to acute and chronic wounds, because PEG-BPEI + antibiotic combinations can kill susceptible and resistant bacteria in their biofilm and planktonic environments. Both 600 Da BPEI and PEG-BPEI disrupt biofilms 31,34,35,37 and disable resistance mechanisms of lab-strains and clinical isolates of multidrug resistant P. aeruginosa, 33,35,37 MRSA, [29][30][31]33,34 and MRSE. 32,36 The data presented here demonstrate that the possible utility of PEG-BPEI potentiators can be expanded to life-threatening CRE infections.…”

“…31,35,36 The antibiofilm properties of 600 Da BPEI is associated with biofilm formation inhibition and an extracellular polymeric substance (EPS)-disruption mechanism. 34,36 This current work expands not only the potential utility of these potentiators against infectious pathogens but also our understanding of the multifunction nature of these compounds.…”