Can microbial cells develop resistance to oxidative stress in antimicrobial photodynamic inactivation?
Introduction
Microorganisms have existed on the earth for more than 3.8 billion years and exhibit the greatest genetic and metabolic diversity of any known life form. They are an important component of the biosphere and serve a vital role in the maintenance of ecosystems. In order to survive, they have evolved mechanisms that enable them to respond to selective pressure exerted by a range of different environments and competitive challenges. Humans have continuously exposed pathogenic microbial populations to antibiotics, antiseptics, and other antimicrobial agents, in attempts to control infectious disease. These microorganisms have then responded by developing a variety of resistance mechanisms to escape this offensive against their survival. Currently, antimicrobial resistance among bacteria, viruses, parasites, and other disease-causing organisms is a serious worldwide threat to management of infectious disease.
Antibiotics were discovered in the middle of the 20th century, and almost immediately reduced the threat of infectious bacterial diseases, which had devastated the human population for centuries. But, surprisingly soon after the discovery of penicillin in 1940, a number of treatment failures and isolation of some bacterial strains such as staphylococci which were no longer sensitive to penicillin started to occur. This marked the beginning of the era of antibiotic resistance (Walsh, 2000).
Resistance can be categorized into two mechanisms.
- A.)
Intrinsic or natural resistance whereby microorganisms naturally either do not possess the appropriate target sites for the specific drug (and therefore the drug does not affect them), or they naturally have only low permeability to those agents, because of the differences in the chemical nature of the drug and the microbial membrane structures. This is particularly relevant for those antibiotics that require entry into the microbial cell in order to effect their action.
- B.)
Acquired resistance whereby a naturally susceptible microorganism develops mechanisms that prevent it from being affected by the drug.
Acquired resistance mechanisms can occur through various ways (summarized in Fig. 1) (Fluit et al., 2001).
- –
the presence of an enzyme that inactivates the antimicrobial agent
- –
a mutation in the antimicrobial target of the agent, which reduces the binding of the antimicrobial agent
- –
post-transcriptional or post-translational modification of the antimicrobial target of the agent, which reduces binding of the antimicrobial agent
- –
reduced uptake of the antimicrobial agent into the cell
- –
active efflux of the antimicrobial agent out of the cell
Resistance elements can be acquired by transmission of free (naked) DNA from one bacterial species to another bacterial species (horizontal gene transfer). Genes responsible for antibiotic resistance in one species of bacteria can be transferred to another species of bacteria through various mechanisms such as F-pilus generation as well as via bacteriophages (Davies and Davies, 2010).
Although antimicrobial resistance is a naturally occurring biological phenomenon, it is often enhanced as a consequence of the adaptation forced upon microbes by continuous or repeated exposure to antimicrobial agents used to prevent or treat infections in humans or livestock, and the widespread routine use of disinfectants in farms, hospitals, and households (Walsh, 2000). It is now accepted that excessive antimicrobial use is the single most important factor responsible for increased antimicrobial resistance (Aarestrup et al., 2001, Byarugaba, 2004)
In 2015 the O’Neill report garnered much international attention when it delivered the alarming forecast that by 2050 (if nothing were done to stem the growth of multi-drug-resistant bacteria) there would have been 300 million premature deaths that would have cost the world economy $100 trillion (O'Neill, 2015).
The current worldwide increase in drug-resistant bacteria and the simultaneous decline in efforts by both academic laboratories and pharmaceutical companies directed towards the discovery of new antibacterial agents to combat resistant strains now poses a serious threat to the treatment of life-threatening infections. Therefore, it is necessary to develop novel non-invasive and non-toxic antimicrobial strategies that act more efficiently and faster than the current antibiotics, and to which pathogens will not easily develop resistance (Taylor et al., 2002). One promising alternative to current antibiotics is antimicrobial photodynamic inactivation (APDI).
Section snippets
Antimicrobial photodynamic inactivation
APDI is defined as the application of a non-toxic dye known as a photosensitizer (PS), which can be photo-activated with light of the appropriate wavelength in the presence of oxygen to generate cytotoxic reactive oxygen species (ROS) such as singlet oxygen and/or free radicals (Hamblin, 2016, Hamblin and Hasan, 2004, Huang et al., 2010).
The process is initiated when a ground state PS (S0) absorbs light of an appropriate wavelength and is converted into an electronic excited singlet state (S1).
Oxidative stress
Microbial life first evolved in a world without oxygen and was rich with reduced iron. By three billion years ago, microbial life forms shared basic biochemical mechanisms and a common metabolic system, which persist even today. The subsequent oxygenation of the atmosphere by photosynthetic organisms created a disaster for primitive life: oxygen is a reactive chemical species, and organisms had to develop strategies to defend themselves against it (Anbar, 2008).
Molecular oxygen (O2) is small
Can resistance develop after sub-lethal APDI?
It is known that repeated usage of antimicrobial agents at low (sub-lethal) concentrations may lead to the development of bacterial population that are more resistant (or at least more tolerant) to higher concentration of these agents (McMahon et al., 2008).
If APDI was used in the treatment of infections and the PS would reach the target site at only sub-lethal concentrations, and was therefore activated by light producing sub-lethal of ROS, any microorganism viable at the site of infection
Mechanisms determining bacterial susceptibility to APDI
Studies have focused on bacterial protection from radical-type oxygen species such as superoxide and hydrogen peroxide. However, the mechanism by which bacteria respond to APDI-mediated stresses remains relatively unknown (Ziegelhoffer and Donohue, 2009).
Biofilm resistance to APDI
A structured consortium of microbial cells (mostly bacteria or fungi) attached onto a living or inert surface is formed by the cells sticking to each other where they are surrounded by the self-produced extracellular polymeric matrix (composed of polysaccharides, proteins, lipids, and extracellular DNA) and is known as a biofilm (Fig. 5). The formation of biofilm is considered an adaptation of microbes to hostile environments (de la Fuente-Nunez et al., 2013, Hall-Stoodley et al., 2004).
Conclusion
APDI is an exciting new approach for the selective inactivation and eradication of microbial pathogens. As antibiotic resistance becomes an even greater issue, APDI will likely be introduced more widely into the clinical setting, however, it is crucial that APDI efficacy be practically evaluated.
The studies mentioned in this work have attempted to model and evaluate possible bacterial resistance mechanisms to APDI. While antibiotics generally work on a “key-and-lock” principle, with each drug
Acknowledgements
MRH was funded by US NIHR01AI050875 and R21AI121700. Nasim Kashef was supported by University of Tehran.
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