Antimicrobial blue light: A ‘Magic Bullet’ for the 21st century and beyond?

Abstract

Over the past decade, antimicrobial blue light (aBL) at 400 − 470 nm wavelength has demonstrated immense promise as an alternative approach for the treatment of multidrug-resistant infections. Since our last review was published in 2017, there have been numerous studies that have investigated aBL in terms of its, efficacy, safety, mechanism, and propensity for resistance development. In addition, researchers have looked at combinatorial approaches that exploit aBL and other traditional and non-traditional therapeutics. To that end, this review aims to update the findings from numerous studies that capitalize on the antimicrobial effects of aBL, with a focus on: efficacy of aBL against different microbes, identifying endogenous chromophores and targets of aBL, Resistance development to aBL, Safety of aBL against host cells, and Synergism of aBL with other agents. We will also discuss our perspective on the future of aBL.

Introduction

At the beginning of the 20th century, a pioneering physician and Nobel Laureate in the field of chemotherapeutics, Paul Ehrlich, developed the ‘Magic Bullet’ concept. He defined a ‘magic bullet’ as an antimicrobial agent capable of selective destruction of pathogenic microorganisms. Paul Ehrlich hoped to develop a therapeutic strategy that eradicated infectious agents but did not harm the host [1]. In 1910, Ehrlich revolutionized chemotherapeutics, with his work culminating in the development of the first antibiotic ‘magic bullet’ arsphenamine (also known as Salvarsan or compound 606) that was capable of successfully treating both Syphilis and African Trypanosomiasis [2], [3]. Although the search was exhaustive, for the next 20 years, there would be no further antimicrobial ‘magic bullets’ discovered. Some 20 years later, in a London laboratory belonging to the bacteriologist Alexander Fleming, an accidental discovery was made that would revolutionize medicine for decades to come [4], [5], [6].

Fleming had returned from vacation when he noticed an invading mold present on agar plates cultured with Staphylococci. What caught his eye, was that there was a clear zone of inhibition present between the mold (later confirmed to belong to the genus Penicillium) and bacterial culture. This led him to conclude that the mold produced an antimicrobial substance that inhibited growth of the Staphylococci. Although he published his results in 1929 [7], he was unable to purify the unstable compound, which he named penicillin, but made it available to all who were interested to attempt to isolate penicillin for clinical use. Enthusiasm for the novel antibacterial compound began to wane in the early 1930s, and it would be more than a decade before any clinical application of penicillin would be achieved [4], [5], [6].

Since the clinical applicability of penicillin was first validated, numerous classes of highly effective antibiotics have been discovered [8]. While there are many highly effective antibiotics present on the market, they all suffer from one serious drawback, resistance development [9]. Antimicrobial resistance occurs when microbes are no longer susceptible to treatment with an antimicrobial. More specifically, we consider microbes to be resistant to antibiotics when concentrations necessary to inhibit their growth rise above a threshold that would be considered unsafe for clinical application, outside the therapeutic window, and thus beyond the ‘magic bullet’ criteria [10]. It is well established that over-exposure of bacteria to sub-lethal concentrations of antibiotics rapidly induces resistance development [11]. In fact, in early testing over a decade before clinical validation, Alexander Fleming warned of future resistance development to penicillin [12].The induction of single nucleotide polymorphisms at target sites of antibiotics is a common occurrence, although there are a multitude of antibiotic resistance mechanisms, including expression of antibiotic specific efflux pumps, enzymes etc [13].

This propensity for resistance development is ubiquitous among all classes of antibiotics, and historically, the time taken between the development of novel antibiotics and the generation of antibiotic resistant phenotypes is remarkably short. For example, methicillin, which is a β-lactam antibiotic that belongs to the penicillin class, that is tolerant to penicillinases, was developed in 1959 [14]. In 1960, there were already reports of clinical specimens of methicillin-resistant Staphylococcus aureus, giving rise to the ‘superbug’ known as MRSA [15]. Thus, while it is undeniable that conventional antibiotics fit Ehrlich’s criteria of ‘magic bullets’, it is likely that as we enter the post-antibiotic era, that this characterization may be short lived. It is unquestionable that an innovative ‘magic bullet’ capable of selective antimicrobial effects that does not succumb to resistance generation is essential.

Antimicrobial blue light (aBL; 400 – 470 nm wavelength) has been shown to be an effective ‘drug-free’ approach that induces potent microbicidal effects. The accepted hypothesis for aBL mediated killing is through photoexcitation of endogenous porphyrins, which result in the generation of intracellular reactive oxygen species (ROS) that induces membrane damage, DNA damage, lipid peroxidation, etc. (Fig. 1) [16]. In addition, our laboratory demonstrated that phototoxic effects of aBL are highly selective against bacteria, with mammalian cells being comparably less susceptible. We attributed this high selectivity to the high concentration of porphyrins within bacteria, relative to mammalian cells. By Ehrlich’s definition, aBL indeed fits the criteria of ‘magic bullet’. Since we published our last aBL review in 2017 [16], there have been numerous novel studies that have exploited aBL. This review aims to update the findings from the new studies including, efficacy of aBL against different microbes, identifying endogenous chromophores and targets of aBL, resistance development to aBL, safety of aBL against host cells, and synergism of aBL with other agents. Our review is limited to peer-reviewed studies that have exploited aBL as a standalone therapeutic, or in combination with other antimicrobials. Therefore, studies that exclusively exploit aBL in the presence of exogenous photosensitizers are excluded.