Hemithioindigo‐Based Visible Light‐Activated Molecular Machines Kill Bacteria by Oxidative Damage

Abstract

Antibiotic resistance is a growing healththreat. There is an urgent and critical need to develop new antimicrobial modalities and therapies. Here, a set of hemithioindigo (HTI)-based molecular machines capable of specifically killing Gram-positive bacteria within minutes of activation with visible light (455 nm at 65 mW cm −2 ) that are safe for mammalian cells is described. Importantly, repeated exposure of bacteria to HTI does not result in detectable development of resistance. Visible light-activated HTI kill both exponentially growing bacterial cells and antibiotic-tolerant persister cells of various Gram-positive strains, including methicillin-resistant S. aureus (MRSA). Visible light-activated HTI also eliminate biofilms of S. aureus and B. subtilis in as little as 1 h after light activation. Quantification of reactive oxygen species (ROS) formation and protein carbonyls, as well as assays with various ROS scavengers, identifies oxidative damage as the underlying mechanism for the antibacterial activity of HTI. In addition to their direct antibacterial properties, HTI synergize with conventional antibiotics in vitro and in vivo, reducing the bacterial load and mortality associated with MRSA infection in an invertebrate burn wound model. To the best of the authors' knowledge, this is the first report on the antimicrobial activity of HTI-based molecular machines.

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study

“…aureus within 15 min. Noticeably, ROS content produced by 200 μg/mL Shik-Fe NPs was even higher than that of 50 μg/mL hydrogen peroxide . Since Shik-Fe NPs killed the bacteria by impacting their integrity, it could kill both Gram-positive and Gram-negative bacteria in theory.…”

“…Noticeably, ROS content produced by 200 μg/mL Shik-Fe NPs was even higher than that of 50 μg/ mL hydrogen peroxide. 34 Since Shik-Fe NPs killed the bacteria by impacting their integrity, it could kill both Gram-positive and Gram-negative bacteria in theory. Shik-Fe NPs inhibited bacterial activity by a slow-release effect and thus gave a more persistent inhibition efficacy compared with Shik.…”

Molecular Jackhammers Eradicate Cancer Cells by Vibronic-Driven Action

“…2 We have more recently studied visible-light-activated Dube-hemithioindigo switches and motors that operate in the kHz regime, 3 and although still these are too slow to mechanically kill cells in our studies, they can induce ROS resulting in slower apoptotic cellular death. 4 (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…2 We have more recently studied visible-light-activated Dube-hemithioindigo switches and motors that operate in the kHz regime, 3 and although still these are too slow to mechanically kill cells in our studies, they can induce ROS resulting in slower apoptotic cellular death. 4 3 While UV and visible light have only hundreds of microns to 1 mm of light penetration through human tissue (skin, muscle, fat), the NIR window of 650 nm to 900 nm, also known as the optical therapeutic window, is ideally suited for in vivo applications because of minimal light absorption by hemoglobin and water with significant penetration through human tissue reaching ~10 cm. 5 We have previously exploited two-photon NIR activation of Feringa-type motors for inducing rapid cellular necrosis, but that technique requires large laser-generated fluxes of photons and hence the depth of penetration is shallow, ~0.5 mm, and the area of coverage is restricted to smaller-sized domains, impractical for broad clinical translation.…”

Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload

“…Synthetic nanomaterials that are not targeted by the natural defensive arsenal of microorganisms represent an unconventional approach to treating infections refractory to standard antimicrobials. [ 12 , 13 ] Molecular machines (MMs) ( Figure 1 A ) are examples of stimuli‐responsive compounds that, in response to light, undergo a sequential unidirectional conformational change, generating a drill‐like motion that can propel the molecule through lipid bilayers. [ 14 ] These stimuli‐responsive systems are particularly promising because they enable antimicrobial attack using a mechanical mechanism at the molecular scale.…”