Improved nanoscale drills kill bacteria directly and revive existing antibiotics

Molecular machines that kill infectious bacteria have been designed to work with a more clinically useful light source of energy. The latest iterations of these synthetic nanoscale or molecular machinery (MM), developed by researchers at Rice University, are activated by visible light rather than ultraviolet (UV), as in earlier versions. Tests of burn-related bacterial infections in living preclinical models have confirmed that the new MMS can effectively kill bacteria.

Six variants of molecular machines were successfully tested by chemist Rice James Tour, PhD and team. They were all able to punch holes in the membranes of gram-negative and gram-positive bacteria in just two minutes. And because bacteria have no natural defense against such mechanical intruders, they are unlikely to develop resistance, scientists believe they offer a strategy that could be used to kill bacteria that have become resistant to standard antibacterial treatments. “I’m telling students that when I’m my age, antibiotic-resistant bacteria will make COVID-19 look like a walk in the park,” Tour said. “Antibiotics will not be able to prevent 10 million people from dying from bacterial infections each year.” But this will really stop them. “

As with previous versions, new molecular machines could also help improve the effectiveness of antibacterial drugs. “Drilling through the membranes of microorganisms allows otherwise ineffective drugs to penetrate cells and overcome the beetle’s own or acquired antibiotic resistance,” said co-investigator Ann Santos, PhD.

The tour, along with colleagues including Rice alumni and first author Santos and Dongdong Liu, PhD, reported on their developments in Scientific advances, in an article entitled “Light-Activated Molecular Machines are fast-acting, broad-spectrum, membrane-targeting antibacterial agents,” in which they concluded that at therapeutic doses, synthetic MMs were able to “greatly outperform conventional antibiotics.” The team concluded: “Visible light-activated MMs represent a new antibacterial mode of action on a mechanical scale that does not occur in nature and to which the development of resistance is unlikely.

Antimicrobial resistance (AMR) is one of the biggest challenges people face, the authors wrote. “AMR is currently responsible for 700,000 deaths a year. By 2050, 10 million lives worldwide will be at risk from drug-resistant infections each year. The problem is increasingly urgent as drug-resistant bacteria continue to thwart existing antibiotics, while the development of new antimicrobials is “almost stagnant,” the team continued. “Since the late 1980s, no new class of antibiotics against Gram-negative bacteria has been approved, and only one in four antibiotics in clinical development is a new class of drugs or acting through a new mechanism of action.” And because most antibiotics being developed are potentially sensitive to the same resistance mechanisms that make existing drugs ineffective, there is an “urgent need” to develop safe and effective new antimicrobial agents that can help prevent the development of resistance while maintaining the viability of existing drugs. antibiotics.

The diagrams show two variants of light-activated molecular machines developed at Rice University that drill and destroy antibiotic-resistant bacteria. The machines could be useful in combating infectious skin diseases. [Tour Research Group/Rice University]

Synthetic molecular motors or molecular machines are molecular structures that can rotate in one direction in response to stimuli, leading to mechanical action, the authors explained. “Among the stimuli that can activate MM, light is particularly appealing due to its non-chemical and non-invasive nature and ease of control,” they noted. When a molecule is irradiated at the correct wavelength, it rotates in one direction, resulting in a rapid drilling-like motion that can drive it through the lipid bilayer.

But while MMs have proven promising for applications ranging from drug delivery to chemo- or antimicrobial therapy, the ultraviolet (UV) radiation required to activate them has limited their clinical utility because prolonged exposure to UV radiation can be harmful to humans.

Rice lab has been improving its MM technology for years. The machines are based on Nobel Prize-winning work by Bernard Feringa, PhD, who in 1999 developed the first molecule with a rotor and made the rotor rotate reliably in one direction. Tour and his team presented their advanced training in 2017 Nature paper.

The new version draws energy from visible but still bluish light of 405 nanometers, which rotates the rotors of molecules at a rate of two to three million times per second. The team achieved the activation of visible light by adding a nitrogen group. “The molecules have been further modified with various amines in either the stator or rotor part of the molecule to promote a connection between the protonated amines of the machines and the negatively charged bacterial membrane,” said Liu, who is now a scientist. at Arcus Biosciences.

Rice’s first tests with new molecules in burn infection models have confirmed their ability to kill bacteria quickly, including methicillin resistance. Staphylococcus aureusa common cause of skin and soft tissue infections, which accounted for more than 100,000 deaths in 2019.Acinetobacter baumannii and S. aureus) in the burn infection model, ”the researchers said.

The transmission electron microscope image shows Escherichia coli bacteria at various stages of degradation after exposure to light-activated molecular drills developed at Rice University. The machines are able to drill into the membranes of antibiotic-resistant bacteria and kill them in a matter of minutes. [Image by Matthew Meyer/Rice University]

The researchers also found that the new MMs effectively break down biofilms and persistent cells that become dormant to avoid antibacterial drugs. “Even though an antibiotic kills most of the colony, there are often a few persistent cells that don’t die for some reason,” Tour said. “But that exercise doesn’t matter.”

The authors further stated: “Persister cells are defined as transient antibiotics of a tolerant fraction of bacterial populations that are metabolically inactive or dormant. MMs were also able to significantly reduce the number of cells and biomass of established biofilms P. aeruginosa and S. aureus. “

Other researchers have suggested that the wavelength light used for the new MM has mild antibacterial properties per se, but the addition of molecular machines overwhelms it, said Tour, who suggested bacterial infections such as those suffered by burn victims and people with gangrene. will be the first goals.

As with previous versions, the new machines can also be used to revive antibacterial drugs that are otherwise considered ineffective. “… MM permeability enhances the effect of conventional antibiotics at sublethal doses,” Rice said. “Drilling the membranes of microorganisms allows otherwise ineffective drugs to penetrate cells and overcome the beetle’s own or acquired antibiotic resistance,” said Santos, who is the third year of a postdoctoral global scholarship that brought her to Rice for two years and continues. at the Health Research Institute in the Balearic Islands in Palma, Spain.

The lab is working to better target bacteria to minimize damage to mammalian cells by attaching bacterial-specific peptide tags to the drills to direct them to pathogens of interest. “But even without that, the peptide can be applied to the site of bacterial concentration, as in the area of ​​burns,” Santos said.

The authors summarized their reported studies: “Together, these results suggest that under the experimental conditions examined, the antibacterial effects induced by MM can be attributed to the rapid one-way rotation of MM after activation by light resembling drilling. the molecule revolves around a central olefinic bond and drives the molecule across the membrane. The subsequent leakage of cell contents and the loss of membrane potential will eventually culminate in the death of the bacterial cell. “

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