Editors' ChoiceANTIBIOTIC RESISTANCE

Drilling down in the fight against bacterial superbugs

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaba2901
DOI: 10.1126/scitranslmed.aba2901

Abstract

Light-activated molecular nanomachines can resensitize antibiotic-resistant bacteria to antibiotics by drilling holes in their cell wall.

One of the most alarming threats to public health worldwide is the increasing prevalence of infectious bacteria that have acquired resistance to antibiotics. For example, strains of Klebsiella pneumoniae, a common cause of hospital-acquired infections, are now resistant to carbapenem antibiotics. Carbapenems kill bacteria by diffusing through porins in the outer membrane of the cell wall and subsequently binding to proteins essential for cell wall synthesis. One way that K. pneumoniae strains have acquired carbapenem resistance is by mutating or losing porins, thereby blocking access of the drug to its target.

To bypass this mechanism of resistance, Glabadage et al. treated K. pneumoniae with synthetic molecules known as “molecular nanomachines.” Analogous to a drill, these molecules comprise a stationary component and a rotor that is activated by light. These molecules naturally diffuse into lipid bilayer membranes, where they drill holes when turned “on” by light. The researchers treated antibiotic-sensitive and antibiotic-resistant strains of K. pneumoniae with a molecular nanomachine that rotates 2 to 3 million times per second. After exposure to light in vitro, the viability of both strains was reduced compared with no treatment or treatment with molecular nanomachines that rotated only 1.8 times per hour. The authors also tested if molecular nanomachines could rescue the effectiveness of meropenem, a carbapenem antibiotic. As predicted, treatment with the fast molecular nanomachine and light increased the susceptibility of the antibiotic-resistant strain of K. pneumoniae to meropenem in vitro.

One advantage of molecular nanomachines is their ability to nonselectively embed into lipid bilayer membranes, indicating they would likely have broad-spectrum effectiveness. However, this nonselectivity is also a disadvantage because they could similarly embed and puncture the membranes of mammalian cells, including the healthy cells in a patient. To combat this, mechanisms to target molecular nanomachines to specific pathogens are currently under development. Although refinement of safety and efficacy and extensive in vivo testing is still needed, this study suggests that a combination therapy of light-activated molecular nanomachines and existing antibiotics holds promise as an exciting new strategy for evading some of the defense mechanisms developed by bacterial superbugs.

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