Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria

Area of Science:

• Antimicrobial resistance
• Bacterial cell wall
• Drug discovery

Background:

• Gram-positive bacteria lack lipopolysaccharide, rendering polymyxin antibiotics ineffective.
• Polymyxin resistance in Gram-negative bacteria is often linked to lipopolysaccharide modification.
• PBT2, a hydroxyquinoline analog, has previously overcome polymyxin resistance in Gram-negative bacteria.

Purpose of the Study:

• To investigate PBT2's ability to overcome intrinsic polymyxin resistance in Gram-positive bacteria.
• To evaluate the efficacy of PBT2 in combination with zinc and colistin against Gram-positive pathogens.
• To explore the mechanism of PBT2's action and its therapeutic potential in a murine infection model.

Main Methods:

• Tested PBT2 combined with zinc against *Streptococcus pyogenes*, *Staphylococcus aureus*, and *Enterococcus faecium*.
• Utilized the M1T1 GAS strain 5448 to demonstrate colistin's bactericidal activity with PBT2 + zinc.
• Assessed resistance development and fitness costs, analyzed metal ion homeostasis, and conducted a murine wound infection model.

Main Results:

• PBT2 + zinc broke intrinsic polymyxin resistance in key Gram-positive pathogens, including MRSA and VRE.
• Colistin with PBT2 + zinc showed bactericidal activity against GAS, with resistance imposing a fitness cost.
• PBT2 + zinc disrupted GAS metal ion homeostasis, reducing manganese content; demonstrated efficacy in a murine skin infection model.

Conclusions:

• PBT2 in combination with zinc can restore polymyxin efficacy against Gram-positive bacteria.
• This combination therapy presents a promising strategy for treating infections caused by resistant Gram-positive pathogens.
• Further research into PBT2 and next-generation polymyxins is warranted for combating Gram-positive bacterial infections.