Alkalinising Agents Revert Bacterial Persisters to Susceptible Phenotype
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Solution Overview
Problem
Current treatments for bacterial infections, particularly those caused by Staphylococcus aureus, are ineffective against persistent and reversible small colony variants (SCVs) and non-replicating persisters due to their ability to hide in low pH environments within host cells, making antibiotics less active and difficult to penetrate.
Innovation Solution
Raising the intracellular pH using agents like chloroquine or bafilomycin A1, combined with bactericidal agents that can target and kill activated bacteria within host cells, effectively reverts SCVs and persisters to a susceptible phenotype.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics are used to treat bacterial infections, then extracellular bacteria can be effectively killed, but intracellular persisters and SCVs hidden in low pH environments remain untreated
Solution Approach 1:
The patent changes the pH parameter of the intracellular environment by administering alkalinizing agents (such as chloroquine or bafilomycin A1) that raise the pH from acidic conditions to neutral or alkaline conditions. This parameter change activates the persisters and SCVs, making them susceptible to antibiotic treatment and thereby resolving the contradiction between effective antibiotic action and persister survival.
2Reliability
If surgery is performed to remove abscesses, then pus and extracellular bacteria can be eliminated, but intracellular bacteria cannot be mechanically removed and persist
Solution Approach 1:
Instead of attempting mechanical removal of intracellular bacteria, the patent changes the physiological parameter (pH) of the intracellular compartment. By raising the intracellular pH to neutralize the acidic environment, the bacteria are activated from their dormant persister state, making them targetable by antibiotics without requiring surgical intervention.
3Productivity
If antibiotics are administered to treat persistent infections, then fast-growing bacteria can be killed, but slow-growing or non-replicating persisters are not affected
Solution Approach 1:
The patent applies preliminary action by first altering the pH environment before antibiotic administration. The alkalinizing agents are given to raise intracellular pH and activate the persisters prior to antibiotic treatment, ensuring that both fast-growing and previously dormant bacteria are in a susceptible state for effective killing.
Solution Approach 2:
By changing the pH parameter from acidic to neutral/alkaline, the metabolic state of the bacteria is altered from dormant to active, thereby enabling antibiotics to effectively kill all bacterial forms regardless of their growth rate.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces the frequency of SCVs and persisters, enhancing the effectiveness of antibiotics and preventing recurrence of infections by making bacteria susceptible to treatment.
Implementation Method 1
administration of an effective amount of an agent that increases the intracellular pH of a host cell and/or of an intracellular compartment of a host cell
Implementation Method 2
administration of an effective amount of a bactericidal agent. Preferably, in the embodiments of the invention, the increase in pH activates a non-replicating intracellular bacterium and the bactericidal agent kills the activated intracellular bacterium
Data Source
AI summary
The present invention relates to the field of medicine, specifically the field of bacterial infection and treatment thereof.