PURPOSE: P128, a phage-derived lysin, exerts antibacterial activity on staphylococci by cleaving the pentaglycine-bridge of peptidoglycan. We sought to determine whether the presence of P128 could re-sensitize drug-resistant bacteria to antibiotics by virtue of its cell wall degrading property. METHODOLOGY: P128 was tested in combination with standard-of-care (SoC) drugs by chequerboard assays on planktonic cells and biofilms of strains individually resistant to these drugs. The bactericidal effect of P128 and drug combinations on planktonic cells and biofilms was measured by c.f.u. reduction assays. A mouse model of MRSA bacteraemia was used to test the efficacy of P128 and oxacillin in combination. RESULTS: A combination of sub-MIC P128 (0.025-0.20 µg ml-1) and 0.5 µg ml-1 of oxacillin resulted in inhibition of bacterial growth in four MRSA strains. Similar results were seen with all the other drugs tested, wherein sub-MIC of P128 re-sensitized S. aureus and CoNS strains to SoC drugs. The chequerboard assays on strains of S. aureus and CoNS showed that combinations of P128 and antibiotics consistently inhibited bacterial growth on biofilms. Data from scanning electron microscopy and c.f.u. reduction assays on drug-resistant S. aureus and CoNS demonstrated that sub-MICs of P128 and SoC antibiotics could kill biofilm-embedded bacteria. In vivo, a combination of sub-therapeutic doses of P128 and oxacillin could help protect animals from fatal bacteraemia. CONCLUSION: The ability of P128 to re-sensitize bacteria to SoC drugs suggests that combinations of P128 and SoC antibiotics can potentially be developed to treat infections caused by drug-resistant strains of staphylococci.
PURPOSE:P128, a phage-derived lysin, exerts antibacterial activity on staphylococci by cleaving the pentaglycine-bridge of peptidoglycan. We sought to determine whether the presence of P128 could re-sensitize drug-resistant bacteria to antibiotics by virtue of its cell wall degrading property. METHODOLOGY:P128 was tested in combination with standard-of-care (SoC) drugs by chequerboard assays on planktonic cells and biofilms of strains individually resistant to these drugs. The bactericidal effect of P128 and drug combinations on planktonic cells and biofilms was measured by c.f.u. reduction assays. A mouse model of MRSA bacteraemia was used to test the efficacy of P128 and oxacillin in combination. RESULTS: A combination of sub-MIC P128 (0.025-0.20 µg ml-1) and 0.5 µg ml-1 of oxacillin resulted in inhibition of bacterial growth in four MRSA strains. Similar results were seen with all the other drugs tested, wherein sub-MIC of P128 re-sensitized S. aureus and CoNS strains to SoC drugs. The chequerboard assays on strains of S. aureus and CoNS showed that combinations of P128 and antibiotics consistently inhibited bacterial growth on biofilms. Data from scanning electron microscopy and c.f.u. reduction assays on drug-resistant S. aureus and CoNS demonstrated that sub-MICs of P128 and SoC antibiotics could kill biofilm-embedded bacteria. In vivo, a combination of sub-therapeutic doses of P128 and oxacillin could help protect animals from fatal bacteraemia. CONCLUSION: The ability of P128 to re-sensitize bacteria to SoC drugs suggests that combinations of P128 and SoC antibiotics can potentially be developed to treat infections caused by drug-resistant strains of staphylococci.
Entities:
Keywords:
CoNS; MRSA; P128; animal efficacy; biofilms; drug resistant Staphylococcus; phage-derived ectolysin; synergy with antibiotics
Authors: Navin Kumar Verma; Si Jia Tan; John Chen; Hanrong Chen; Muhammad Hafiz Ismail; Scott A Rice; Pablo Bifani; Sukumar Hariharan; Vivek Daniel Paul; Bharathi Sriram; Linh Chi Dam; Chia Ching Chan; Peiying Ho; Boon Chong Goh; Shimin Jasmine Chung; Kenneth Choon Meng Goh; Shu Hua Thong; Andrea Lay-Hoon Kwa; Adam Ostrowski; Thet Tun Aung; Halimah Razali; Shermaine W Y Low; Mani Shankar Bhattacharyya; Hemant K Gautam; Rajamani Lakshminarayanan; Thomas Sicheritz-Pontén; Martha R J Clokie; Wilfried Moreira; Maurice Adrianus Monique van Steensel Journal: Phage (New Rochelle) Date: 2022-03-18