Expanding the Spectrum of Antibiotics Capable of Killing Multidrug‐Resistant <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i>

Lam, Anh K.; Panlilio, Hannah; Pusavat, Jennifer; Wouters, Cassandra L.; Moen, Erika L.; Brennan, Robert; Rice, Charles V.

doi:10.1002/cmdc.202000239

Cited by 13 publications

(36 citation statements)

References 58 publications

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“… 1 , 3 − 8 Low-molecular-weight (600 Da) branched polyethylenimine (600 Da BPEI) has the ability to overcome AMR in staphylococci and Pseudomonas aeruginosa , potentiating penicillins, carbapenems, cephalosporins, and macrolides. 4 , 9 − 14 Nevertheless, the presence of primary amines creates toxicity issues that are paramount. In vivo toxicity issues are mitigated by attaching a low-molecular-weight polyethylene glycol (PEG) group to 600 Da BPEI (PEG-BPEI).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Bacterial biofilms, often impenetrable to antibiotic medications, are a leading cause of poor wound healing. The prognosis is worse for wounds with biofilms of antimicrobial-resistant (AMR) bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), and multi-drug resistant Pseudomonas aeruginosa (MDR-PA). Resistance hinders initial treatment of standard-of-care antibiotics. The persistence of MRSA, MRSE, and/or MDR-PA often allows acute infections to become chronic wound infections. The water-soluble hydrophilic properties of low-molecular-weight (600 Da) branched polyethylenimine (600 Da BPEI) enable easy drug delivery to directly attack AMR and biofilms in the wound environment as a topical agent for wound treatment. To mitigate toxicity issues, we have modified 600 Da BPEI with polyethylene glycol (PEG) in a straightforward one-step reaction. The PEG–BPEI molecules disable β-lactam resistance in MRSA, MRSE, and MDR-PA while also having the ability to dissolve established biofilms. PEG-BPEI accomplishes these tasks independently, resulting in a multifunction potentiation agent. We envision wound treatment with antibiotics given topically, orally, or intravenously in which external application of PEG–BPEIs disables biofilms and resistance mechanisms. In the absence of a robust pipeline of new drugs, existing drugs and regimens must be re-evaluated as combination(s) with potentiators. The PEGylation of 600 Da BPEI provides new opportunities to meet this goal with a single compound whose multifunction properties are retained while lowering acute toxicity.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…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.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…51 We reported potentiation across antibiotic classes by lowering LPS barriers, which enhances passive diffusion and porin-mediated drug influx mechanisms. 33,35 This paradigm applies equally to increasing the influx of β-lactamase inhibitors, such as tazobactam, and should also improve the uptake of effluxpump inhibitors. These complementary MOAs enhance the value of PEG-BPEI, which also disrupts biofilms, 37 an underlying pathology that contributes to delayed healing.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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The rise of life-threatening carbapenem-resistant Enterobacteriaceae (CRE) infections has become a critical medical threat. Some of the most dangerous CRE bacteria can produce enzymes that degrade a wide range of antibiotics, including carbapenems and β-lactams. Infections by CRE have a high mortality rate, and survivors can have severe morbidity from treatment with toxic last-resort antibiotics. CRE have mobile genetic elements that transfer resistance genes to other species. These bacteria also circulate throughout the healthcare system. The mobility and spread of CRE need to be curtailed, but these goals are impeded by having few agents that target a limited range of pathogenic CRE species. Against CRE possessing the metallo-β-lactamase NDM-1, Klebsiella pneumoniae ATCC BAA-2146 and Escherichia coli ATCC BAA-2452, the potentiation of meropenem and imipenem is possible with low-molecular weight branched polyethylenimine (600 Da BPEI) and its poly(ethylene glycol) (PEG)ylated derivative (PEG-BPEI) that has a low in vivo toxicity. The mechanism of action is elucidated with fluorescence assays of drug influx and isothermal calorimetry data showing the chelation of essential Zn2+ ions. These results suggested that 600 Da BPEI and PEG-BPEI may also improve the uptake of antibiotics and β-lactamase inhibitors. Indeed, the CRE E. coli strain is rendered susceptible to the combination of piperacillin and tazobactam. These results expand the possible utility of 600 Da BPEI potentiators, where previously we have demonstrated the ability to improve antibiotic efficacy against antibiotic resistant clinical isolates of Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis.

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“…[4][5][6][7][8] Likewise, positively charged Branched PolyEthylenImine (BPEI) has been shown to potentiate β-lactam antibiotics against the Gram-positive pathogen methicillin resistant Staphylococcus aureus (MRSA). 9,10 It was proposed that BPEI neutralization of negatively charged polymers on the bacterial cell surface improved permeability. 11 These examples demonstrate that improved permeation to the essential cell wall components can be a powerful modality of reducing intrinsic resistance to small molecule antibacterials and immune proteins.…”

Section: Introductionmentioning

confidence: 99%

Transposon Screen of Surface Accessibility inS. aureus

Ferraro

Pires

2021

Preprint

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Bacterial cell walls represent one of the most prominent targets of antibacterial agents. These agents include natural products (e.g., vancomycin) and proteins stemming from the innate immune system (e.g., peptidoglycan-recognition proteins and lysostaphin). Among bacterial pathogens that infect humans, Staphylococcus aureus (S. aureus) continues to impose a tremendous healthcare burden across the globe. S. aureus has evolved countermeasures that can directly restrict the accessibility of innate immune proteins, effectively protecting itself from threats that target key cell well components. We recently described a novel assay that directly reports on the accessibility of molecules to the peptidoglycan layer within the bacterial cell wall of S. aureus. The assay relies on site-specific chemical remodeling of the peptidoglycan with a biorthogonal handle. Here, we disclose the application of our assay to a screen of a nonredundant transposon mutant library for susceptibility of the peptidoglycan layer with the goal of identifying genes that contribute to the control of cell surface accessibility. We discovered several genes that resulted in higher accessibility levels to the peptidoglycan layer and showed that these genes modulate sensitivity to lysostaphin. These results indicate that this assay platform can be leveraged to gain further insight into the biology of bacterial cell surfaces.

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Expanding the Spectrum of Antibiotics Capable of Killing Multidrug‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Cited by 13 publications

References 58 publications

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

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

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

Transposon Screen of Surface Accessibility inS. aureus

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