Cationic Branched Polyethylenimine (BPEI) Disables Antibiotic Resistance in Methicillin‐Resistant Staphylococcus epidermidis (MRSE)

Abstract

Staphylococcus epidermidis is one of the most prevalent prokaryotic species on human skin and mucosal membranes that constitute the commensal flora. S. epidermidis has become one of the most common causes of primary bacteremia. Infections are difficult to diagnose because the pathogen has natural niches on human skin and the ability to adhere to inanimate surfaces via biofilms. Alarmingly, S. epidermidis has acquired resistance to many antibiotics, which presents a danger to human health. Known as methicillin-resistant S. epidermidis (MRSE), most clinical isolates of MRSE in North America exhibit β-lactam resistance primarily due to the presence of mecA, a gene that bestows β-lactam antibiotic resistance in a manner similar to methicillin-resistant Staphylococcus aureus (MRSA). MecA encodes for expression of penicillin-binding protein 2a (PBP2a), which is absent in β-lactam susceptible strains of S. epidermidis. We can disable this resistance factor in MRSE with 600-Da branched polyethylenimine (BPEI). Cationic BPEI targets anionic wall teichoic acid (WTA), an essential cofactor for proper functioning of PBP2a. We found that BPEI synergizes the activity of β-lactam antibiotics against MRSE. Growth curves suggest that the combination of BPEI and oxacillin is bactericidal. Electron micrographs indicate abnormalities in the cellular septa and cell walls of treated samples. Therefore, first-line clinical treatments can be effective against MRSE when used in combination with BPEI.

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.…”

Antibiofilm Synergy of β-Lactams and Branched Polyethylenimine against Methicillin-Resistant Staphylococcus epidermidis

“…In our previous study, disabling PBP2a with 600 Da BPEI resensitizes MRSE to β -lactams. 11 Here, we investigated a combination of BPEI and β -lactam antibiotics (oxacillin and piperacillin) against biofilms formed by two MRSE strains, MRSE ATCC 35984, and MRSE ATCC 29887. The MICs of BPEI and the antibiotics were found using the antimicrobial challenge plates, which measured the change in OD 600 of planktonic bacteria.…”

“…In this manner, BPEI disabled resistance in MRSE strains, restoring their susceptibility to traditional β -lactam antibiotics. 11 In this report, we further investigate the application of our technology to MRSE biofilms where the EPS contains numerous anionic biomacromolecules. The EPS creates a hydrophobic barrier that increases the tolerance of bacteria toward antimicrobials by reducing or preventing the antibiotics from reaching their target(s).…”

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

“…Thus, PKZ18 and its analogues allow room for modification of the core to adapt to the physical properties needed for the discovery of compounds that permeate the bacterial cell wall, and be used in topical as well as non‐topical formulations. For instance, the optimized PKZ18 family could be useful to combat drug‐resistant infections of the Gram‐positive pathogen S. epidermidis that occur topically in recesses on the human skin and internally where they adhere to device surfaces, prosthetic heart valves, shunts, via biofilms. PKZ18 is elongated and planar, characteristics that render it well‐suited for binding in the major groove of the Specifier Loop.…”

“…[77] Indeed, the set of currently used antimicrobials does not seem to follow such rigid Lipinski patterns, andn either do some humand isease drugs selected for intervention against protein and more recently RNA targets. [78] Thus, PKZ18 and its analoguesa llow room for modification of the core to adapt to the physical properties needed for the discoveryo fc ompounds that permeate the bacterial cell wall, and be used in topical as well as non-topical formulations.F or instance, the optimized PKZ18 family could be useful to combat drug-resistant infections of the Gram-positive pathogen S. epidermidis [79] that occur topically in recesses on the humans kin and internally where they adhere to devices urfaces, prosthetic heart valves, shunts,v ia biofilms.P KZ18 is elongated andp lanar,c haracteristics that render it well-suited for binding in the major groove of the Specifier Loop. In addition, al imited structure-activity exploration was performeda round the norbornyl-thiazole substructure which resulted in additional hit compounds and potentially ac ommon mechanism of action.…”