Reversing Multidrug‐Resistant Escherichia coli by Compromising Its BAM Biogenesis and Enzymatic Catalysis through Microwave Hyperthermia Therapy

Abstract Multidrug‐resistant (MDR) bacteria are emerging and disseminating rapidly, undoubtedly posing an urgent threat to global public health. One particular concern is that MDR Gram‐negative bacteria are immunized to available antibiotics owing to a series of biogenetic effects, including the β‐barrel assembly machine (BAM complex) in the outer membrane, MDR efflux pumps, and enzymatic degradation/modification, which are known to induce antibiotic resistance (AbR). Here, this work identifies that the AbR mechanisms of MDR Escherichia coli become compromised and sensitive again to conventional antibiotics, when the temperature of infected tissues is elevated to ≈50 °C in situ. This thought is realized by the microwave‐driven poly(lactic‐ co ‐glycolic acid) microparticles that may effectively convert electromagnetic radiation to thermal energy. The microwave hyperthermia (MWH) therapy not only interrupts the essential surface‐exposed BamA protein of the BAM complex, but also enhances the permeability of the outer membrane and inhibits the action of MDR efflux pumps. MWH also impairs the hydrogen bond interaction between the catalytic residues of bacterial enzymes and functional groups of antibiotic molecules. Lastly, this work demonstrates these combined inhibitors can revitalize the bactericidal effects of conventional antibiotics in MDR Escherichia coli ‐associated deep tissue infections.