Maggots are fly larvae. Their life cycle goes like this: flies are attracted to food and other rubbish on which they lay their eggs; later the eggs hatch into maggots, which turn into flies. You may be wondering if you have eaten that picnic sandwich which a fly had just landed on (and possibly laid its eggs), whether the eggs and maggots can survive!? Answer: larvae that might be accidentally ingested with food cannot usually survive in the gastrointestinal environment.
Maggots are not all bad however, they play an important role in decomposition, pollinating plants and providing food for other insects. They can also help solve crimes. Surely you remember Gil Grissom’s (from the TV series, CSI: Crime Scene Investigates) obsession with flies and larvae; he uses entomology to identify time of death by calculating the timeline of flies arriving, feeding and laying eggs in decomposing flesh. A lifecycle first demonstrated in 1668, by Italian physician Francesco Redi who showed that maggots do not “just appear” but that maggots turned into flies, which laid eggs that turned into more maggots.
Maggots can also heal wounds. Larval therapy has been known about for hundreds of years. It was used by ancient Mayan civilizations as well as Aboriginal tribes in Australia; even Napolean’s Surgeon in about 1800 noted that certain species of flies helped wounds to heal.
Larval therapy is the use of live, disinfected maggots from specific species of flies that are deliberately put into wounds in order to remove dead necrotic tissue therefore assisting wound healing. The most commonly used species of maggot for medical therapy is Lucilia sericata, the common green bottle fly larva.
Maggots can also heal wounds. Larval therapy has been known about for hundreds of years. It was used by ancient Mayan civilizations as well as Aboriginal tribes in Australia; even Napolean’s Surgeon in about 1800 noted that certain species of flies helped wounds to heal.
Larval therapy is the use of live, disinfected maggots from specific species of flies that are deliberately put into wounds in order to remove dead necrotic tissue therefore assisting wound healing. The most commonly used species of maggot for medical therapy is Lucilia sericata, the common green bottle fly larva.
Green Bottle Fly
BUT, this isn’t a blog about larval therapy… I’ve done that and lots of you went oooh!!! This is a blog about antibiotics!
The “magnificent” thing about the larvae of Lucilia sericata is that they also produce antimicrobial compounds… who would have guessed? Well it actually makes sense if you think about it further. The maggots usually survive in the environments of dead and necrotic tissue; these are potentially hostile places as these conditions are also where bacteria thrive. As these bacteria grow and multiply much faster than the maggots, the bacteria might be expected to out-compete the maggot for resources such as food. In order to stop this happening the maggots have developed a form of defence mechanism against the bacteria, manufacturing lethal compounds which they direct towards the bacteria. This is much the same way as fungi do, which are the traditional source of antimicrobials. Nature is really rather clever in that way.
A recent paper in the Journal of Antimicrobial Chemotherapy (JAC) has described two possible antimicrobials for future development derived from the larvae of Lucilia sericata. The JAC is an excellent scientific journal about antimicrobials but unfortunately this article will not be free to access by all, you’d have to become a member of the British Society for Antimicrobial Chemotherapy (BSAC)… which if you are interested in antimicrobials is a very worthwhile thing to do, but I might be biased as I have been a member of this society for many years. Alternatively the hospital library might be able to get you a copy.
Antimicrobial peptides (AMPs)
The two compounds described in the JAC paper, called LS-sarcotoxin and LS-stomoxyn, are linear cationic antimicrobial peptides (AMPs). AMPs are part of the innate immune response (the primitive part of the immune system which is part of the early response to pathogens) of all living things but they differ between organisms. They have very variable structures and mechanisms of action although cell membranes are a common target. Because of this they are often compared to the antibiotic Colistin which also targets the cell membrane of bacteria.
Having said that, the exact mechanism of action of LS-sarcotoxin and LS-stomoxyn is not actually known. Whilst they may target the cell membrane like Colistin they do not compete for the exact same target as they show synergy with Colistin (the combination is more effective than the sum of the activity of each agent alone).
Spectrum of activity
The paper’s authors tested LS-sarcotoxin and LS-stomoxyn against 114 multidrug resistant (MDR) Gram-negative bacteria isolated from hospital patients in Germany. The majority of the bacteria tested were E. coli, Klebsiella pneumoniae, Enterobacter cloacae and Acinetobacter baumanii. These bacteria are either notorious for being resistant as in the case of A. baumanii, or commonly found to be resistant to many antibiotics. The AMPs from maggots were principally active against Gram-negative bacteria and this makes sense as these are the types of bacteria likely to colonise wounds and dead tissue and the main competitors for the maggots.
The two AMPs have been previously shown to have no activity against Gram-positive bacteria and Candida spp., but that’s fine as it is the fight against Gram-negative bacteria where we really need new antibiotics.
In order to assess experimentally how LS-sarcotoxin and LS-stomoxyn might behave in a human body the AMPs were tested in the presence of sodium chloride and human serum. Surprisingly the addition of sodium chloride and human serum made the AMPs much more effective, reducing the minimum inhibitory concentrations (MICs) by 16-128 times depending on the bacterium tested. This means you would need 16-128 times less antibiotic when using it in the human body and that’s pretty magnificent! Most antibiotics are not affected by sodium chloride or human serum like this.
The “magnificent” thing about the larvae of Lucilia sericata is that they also produce antimicrobial compounds… who would have guessed? Well it actually makes sense if you think about it further. The maggots usually survive in the environments of dead and necrotic tissue; these are potentially hostile places as these conditions are also where bacteria thrive. As these bacteria grow and multiply much faster than the maggots, the bacteria might be expected to out-compete the maggot for resources such as food. In order to stop this happening the maggots have developed a form of defence mechanism against the bacteria, manufacturing lethal compounds which they direct towards the bacteria. This is much the same way as fungi do, which are the traditional source of antimicrobials. Nature is really rather clever in that way.
A recent paper in the Journal of Antimicrobial Chemotherapy (JAC) has described two possible antimicrobials for future development derived from the larvae of Lucilia sericata. The JAC is an excellent scientific journal about antimicrobials but unfortunately this article will not be free to access by all, you’d have to become a member of the British Society for Antimicrobial Chemotherapy (BSAC)… which if you are interested in antimicrobials is a very worthwhile thing to do, but I might be biased as I have been a member of this society for many years. Alternatively the hospital library might be able to get you a copy.
Antimicrobial peptides (AMPs)
The two compounds described in the JAC paper, called LS-sarcotoxin and LS-stomoxyn, are linear cationic antimicrobial peptides (AMPs). AMPs are part of the innate immune response (the primitive part of the immune system which is part of the early response to pathogens) of all living things but they differ between organisms. They have very variable structures and mechanisms of action although cell membranes are a common target. Because of this they are often compared to the antibiotic Colistin which also targets the cell membrane of bacteria.
Having said that, the exact mechanism of action of LS-sarcotoxin and LS-stomoxyn is not actually known. Whilst they may target the cell membrane like Colistin they do not compete for the exact same target as they show synergy with Colistin (the combination is more effective than the sum of the activity of each agent alone).
Spectrum of activity
The paper’s authors tested LS-sarcotoxin and LS-stomoxyn against 114 multidrug resistant (MDR) Gram-negative bacteria isolated from hospital patients in Germany. The majority of the bacteria tested were E. coli, Klebsiella pneumoniae, Enterobacter cloacae and Acinetobacter baumanii. These bacteria are either notorious for being resistant as in the case of A. baumanii, or commonly found to be resistant to many antibiotics. The AMPs from maggots were principally active against Gram-negative bacteria and this makes sense as these are the types of bacteria likely to colonise wounds and dead tissue and the main competitors for the maggots.
The two AMPs have been previously shown to have no activity against Gram-positive bacteria and Candida spp., but that’s fine as it is the fight against Gram-negative bacteria where we really need new antibiotics.
- LS-sarcotoxin showed excellent activity against E. coli, E. cloacae, Klebsiella spp., Salmonella enterica, Citrobacter freundii and Acinetobacter spp., although it had little activity against Pseudomonas aeruginosa.
- LS-stomoxyn on the other hand had good activity against Pseudomonas aeruginosa, A. baumanii and most of the Enterobacteriaceae with the exception of K. pneumoniae.
- Even bacteria which have a lot of resistance mechanisms e.g. to beta-lactams, aminoglycosides and fluoroquinolones were still sensitive to the AMPs
- Neither AMP was active against the Gram-negative bacteria Proteus mirabilis, Stenotrophomonas maltophilia, Morganella morganii or Serratia spp.
In order to assess experimentally how LS-sarcotoxin and LS-stomoxyn might behave in a human body the AMPs were tested in the presence of sodium chloride and human serum. Surprisingly the addition of sodium chloride and human serum made the AMPs much more effective, reducing the minimum inhibitory concentrations (MICs) by 16-128 times depending on the bacterium tested. This means you would need 16-128 times less antibiotic when using it in the human body and that’s pretty magnificent! Most antibiotics are not affected by sodium chloride or human serum like this.
Selection of resistance
Resistance is an emerging threat to all antibiotics so determining early if the target bacteria can easily become resistant to the new antibiotic compound is increasingly prudent! The authors tried to “make” bacteria resistant to the AMPs by serially passaging bacteria against low levels of the AMPs; essentially they grew the bacteria in low concentrations of AMP over 30 days in order to try and select out resistant mutants. Typically when E. coli and P. aeruginosa are passaged with Colistin the bacteria develop a 100x increase in MIC i.e. they would become resistant to normal and high levels of antibiotics. This has been demonstrated by Harvard University in this YouTube video of showing E. coli developing resistance to an antibiotic over only 10 days!
However, with LS-sarcotoxin and LS-stomoxyn neither E. coli nor P. aeruginosa became resistant during a 30 day period, suggesting resistance to these AMPs may not occur readily in real life use.
Are these AMPs toxic?
Maybe this should be the first question asked…but it often isn’t! In the JAC paper the authors undertook a number of experiments to look for toxicity by adding low and high concentrations of the AMPs to cell cultures of human cells. No haemolytic, cardiotoxic or other toxicity issues were demonstrated. In addition, when the AMPs were injected into mice for stability studies, no toxicity was seen. Okay, these are preliminary studies but toxicity at this stage would be the end of this area of research! A dead patient with a cured infection is not a good outcome… sometimes Doctors need to remember this! (See organ failure blog).
So what are the drawbacks to these magnificent maggot compounds?
There are two main drawbacks from this initial study of LS-sarcotoxin and LS-stomoxyn. The first is the lack of activity against ALL Gram-negative bacteria. I know I’m being greedy but with good reason. If LS-sarcotoxin and LS-stomoxyn showed good activity against all of the Enterobacteriaceae then they would be excellent antibiotics for the empirical treatment of Gram-negative infections such as UTIs or intra-abdominal sepsis, however when there are significant Gram-negative bacteria that are NOT COVERED (e.g. P. mirabilis, S. maltophilia, M. morganii, Serratia spp. and P. aeruginosa) then the LS-sarcotoxin and LS-stomoxyn would either have to be used in combination with other antibiotics (which is feasible) or would have to be reserved for when the exact bacterium was known.
The second drawback is much more problematic. LS-sarcotoxin and LS-stomoxyn are unstable in plasma; in the mouse testing the compounds could only be detected for about 5-15 minutes. This is not long enough for them to be active against bacteria in the blood stream. This could be a major problem. Or it may be that the AMPs are binding to protein in the blood and therefore cannot be detected but still have activity; I’m sure there will be further work to fully ascertain the pharmacokinetics.
So it looks like maggots may be the future for anti-Gram-negative antibiotics. Two compounds, LS-sarcotoxin and LS-stomoxyn, derived from the green bottle fly larvae show good activity against many MDR Gram-negative bacteria. I for one look forward to reading the results of the further work to see if these compounds might be suitable as future antibiotics.
Could our new antibiotics look like this...?
Resistance is an emerging threat to all antibiotics so determining early if the target bacteria can easily become resistant to the new antibiotic compound is increasingly prudent! The authors tried to “make” bacteria resistant to the AMPs by serially passaging bacteria against low levels of the AMPs; essentially they grew the bacteria in low concentrations of AMP over 30 days in order to try and select out resistant mutants. Typically when E. coli and P. aeruginosa are passaged with Colistin the bacteria develop a 100x increase in MIC i.e. they would become resistant to normal and high levels of antibiotics. This has been demonstrated by Harvard University in this YouTube video of showing E. coli developing resistance to an antibiotic over only 10 days!
However, with LS-sarcotoxin and LS-stomoxyn neither E. coli nor P. aeruginosa became resistant during a 30 day period, suggesting resistance to these AMPs may not occur readily in real life use.
Are these AMPs toxic?
Maybe this should be the first question asked…but it often isn’t! In the JAC paper the authors undertook a number of experiments to look for toxicity by adding low and high concentrations of the AMPs to cell cultures of human cells. No haemolytic, cardiotoxic or other toxicity issues were demonstrated. In addition, when the AMPs were injected into mice for stability studies, no toxicity was seen. Okay, these are preliminary studies but toxicity at this stage would be the end of this area of research! A dead patient with a cured infection is not a good outcome… sometimes Doctors need to remember this! (See organ failure blog).
So what are the drawbacks to these magnificent maggot compounds?
There are two main drawbacks from this initial study of LS-sarcotoxin and LS-stomoxyn. The first is the lack of activity against ALL Gram-negative bacteria. I know I’m being greedy but with good reason. If LS-sarcotoxin and LS-stomoxyn showed good activity against all of the Enterobacteriaceae then they would be excellent antibiotics for the empirical treatment of Gram-negative infections such as UTIs or intra-abdominal sepsis, however when there are significant Gram-negative bacteria that are NOT COVERED (e.g. P. mirabilis, S. maltophilia, M. morganii, Serratia spp. and P. aeruginosa) then the LS-sarcotoxin and LS-stomoxyn would either have to be used in combination with other antibiotics (which is feasible) or would have to be reserved for when the exact bacterium was known.
The second drawback is much more problematic. LS-sarcotoxin and LS-stomoxyn are unstable in plasma; in the mouse testing the compounds could only be detected for about 5-15 minutes. This is not long enough for them to be active against bacteria in the blood stream. This could be a major problem. Or it may be that the AMPs are binding to protein in the blood and therefore cannot be detected but still have activity; I’m sure there will be further work to fully ascertain the pharmacokinetics.
So it looks like maggots may be the future for anti-Gram-negative antibiotics. Two compounds, LS-sarcotoxin and LS-stomoxyn, derived from the green bottle fly larvae show good activity against many MDR Gram-negative bacteria. I for one look forward to reading the results of the further work to see if these compounds might be suitable as future antibiotics.
Could our new antibiotics look like this...?
Reference
P.S. If you are dreaming of maggots, apparently it means that you are not able to recognise (or deal with) a problem that is bothering you in your waking life... for me these dreams tend to occur on call after dealing with MDR Gram-negative infections!
- Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR Gram-negative bacteria. R. Hirsch, J Wiesner, A Marker, et al. J Antimicrob Chemother 2019; 74: 96-107
P.S. If you are dreaming of maggots, apparently it means that you are not able to recognise (or deal with) a problem that is bothering you in your waking life... for me these dreams tend to occur on call after dealing with MDR Gram-negative infections!
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