Thursday, February 26, 2015 4:36:51 PM
Brilacidin: Resistance may be -- is? -- Futile
(longer post, be forewarned)
Thought folks might be interested in some literature/commentary that gets to the Resistance Q. Have been looking into it for a few weeks.
Below a post from a hyperbolic Polymedix fan (seems like an insider) from 2011. To Landekic's comment that their compounds hardly met a bug they couldn't kill. Whether resistance never develops as this person argued, or will just take a lot longer (my thoughts), is still an open Q. To that end, I included three other relevant cites.
One, published in 2012, covers Host Defensin Peptides (refs PMX-30063, Brilacidin) in the treatment of MRSA; the second, published in 2006, was co-written by Michael Zasloff, the Magainin/Pexiganin [Dipexium Rx's Locilex] (frog skin) discoverer out of Georgetown who expressed initial skepticism re Brilacidin. (See Manmade Defensins... article/excerpt below; have posted before.) And the third is by the Defensin-Mimetics folks out of British Columbia (Hancock).
What most caught my eye, as to the pub'd studies, is that the marshalling of host resources tied to the immune response may be more important in reducing the likelihood of resistance than the ability -- via evolutionary pressure (adaptation) -- for the bug to armor up (so to speak). Synthetic peptides may also have a distinct advantage.
MANMADE DEFENSIN RIPS APART RESISTANT BACTERIA
http://www.newscientist.com/article/dn13924-manmade-defensin-rips-resistant-bacteria-apart.html#.VLW-Y0ZHbCQ
EXCERPT
"For conventional antibiotics, you generally find it takes 100 times more of the antibiotic to kill the bacteria after 9 repeats," says Nick Landekic, Polymedix's chief executive. "We've done 14 repeats with PMX-30063 and there is no change in its potency." "Really exciting" Michael Zasloff at Georgetown University, Washington DC, US, was not involved with the work but plans to follow its progress. "Their compounds are really exciting and look great, but the value of this class will be based on safety." [AND SAFETY HAS BEEN MET] He says there is a chance that PMX-30063 may punch holes in human cells as well as bacterial ones." My concerns are with how it interacts with sites in the body known to be sensitive to damage by positively-charged peptides - areas such as the kidney and middle ear," says Zasloff. [NOPE DIDNT HAPPEN] DeGrado and colleagues think the risk is low, saying their molecule is several thousand times more likely to target bacterial cells than it is to attack mammalian ones. [AND DEGRADO WAS RIGHT]
BLOG POST: BACTERIAL RESISTANCE TO THE PMX MOLECULES
http://pymx.blogspot.com/2011/02/bacterial-resistance-to-pmx-molecules.html?m=1
Frankly, the PolyMedix PMX molecules are simply resistance proof. In order for a bacterium to gain resistance it would have to evolve an entire new plasma membrane with a bilipid structure entirely different from what it’s genetically programed to synthesize and utilize. Dr. DeGrado’s molecules are designed to spontaneously latch on to both the hydrophillic outer layer of the membrane and bore into the hydrophobic interior fatty layer. When this happens, the membrane loses integrity and rips apart. The stuff in the cell is free then to diffuse out. The bacterium is then functionally dead.
To keep any of that from happening, the bacterium must present a different membrane without its peculiar hydrophyllic and hydrophobic layers—which are unique in bacteria compared to unaffected animal (human) cell membranes.
I’ve said it before. There simply cannot be any appearance of bacterial resistance to the PMX molecules.
PolyMedix molecules have no need to get through the plasma membrane of the bacteria. They must merely touch them, and they dissolve, so to speak.
************************************
PolyMedix molecules work—kill bacteria—in ways no existing antibiotic does. Moreover, and crucially, there is no foreseeable means by which any bacterium could evolve resistance. Notice that the PolyMedix lawyers have caused all the information from the company on this point to claim, so to speak, “Resistance is thought to be unlikely...,” or words to that effect. Those of us who know a bit about bacterial genetics and the structure and function of bacterial plasma membranes, know fully that nothing can stop the PolyMedix molecules, regardless.
The seminal phrase (and mechanism) for PMX efficacy is “membrane disruption.” No other antibiotic works this way. Penicillin, and all the rest, have to get themselves inserted inside the bacterium, where they bind on to, or otherwise disrupt crucial molecules, often essential enzymes. The PMX stuff all works from the outside, so no problems getting in.
And this is an important point, too. You mentioned that it took thousands of years for conventional resistance to occur. That’s probably not the case. Most antibiotics originated from naturally occurring molecules, often in soil. They have been confronting bacteria for millennia, and the bacteria already have genes, if expressed, that can fight them off—which they are now doing in MRSA and other resistant bacteria.
Innate, unexpressed resistance to PMX molecules will not exist. PolyMedix molecules are unique. They have on their surfaces a bunch of molecular “sticky points” and adjacent “repellant points” that when bumped against a bacterium, while merely floating around in blood, cause the bacterium’s plasma membrane to spontaneously break apart, the so-called “membrane disruption.” The PMX molecules are little armor-piercing devices that repeatedly poke holes in the bacteria, because of the unique chemistry of bacteria plasma membranes. The bacteria have no way to repair such rapid, almost instantaneous damage, nor do they have any way of making a functioning plasma membrane that does not have the “sticky spots.” It’s no-win for the germs. Period.
Another Post of his worth a look--Polymedix -vs- Tetraphase
http://pymx.blogspot.com/2011/02/posts-from-falconer66a-polymedix-vs.html?m=1
2) BEYOND CONVENTIONAL ANTIBIOTICS FOR THE FUTURE TREATMENT OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS INFECTIONS: TWO NOVEL ALTERNATIVES (2012)
http://femsim.oxfordjournals.org/content/65/3/399.long
EXCERPTS
The investigation of alternative therapeutic agents with novel mechanisms of action remains largely an activity for academic researchers and small biotechnology companies. This type of research has resulted in preclinical developments in the areas of innate immune defence peptides and antipathogenic agents with potential as novel anti-MRSA therapeutics. For example, cationic peptides offer multiple and alternative modes of action that may circumvent the problem of antimicrobial resistance. Significant improvements, to the chemistry of such peptides, have increased their attractiveness in terms of pharmacokinetics, toxicity and cost.
[...]
A nonpeptide structural mimetic of defensin, with low toxicity, PMX-30063D, is currently in clinical development for infections involving S. aureus.
[...]
It has been suggested that HDPs, if developed as MRSA anti-infectives, would have low propensity to select resistant mutants compared with classical antibiotics. This is based on the multiple mechanisms of action of HDPs. However, bacteria and the human host have co-evolved, and S. aureus adaptations have been described for a small number of host defence peptides. For example, reduced susceptibility to defensin and protegrins has been demonstrated in S. aureus which is mediated by the incorporation of positively charged l-lysine into the cytoplasmic membrane and is catalysed by the product of the mprF gene (Peschel et al., 2001; Ernst et al., 2009). Interestingly, this membrane modification also contributes to S. aureus resistance to the CAMP-like agent daptomycin, which is currently in clinical use for MRSA infections. An investigation of the evolution of CA-MRSA shows that USA 300 and USA500 strains are more resistant to the innate immune defence peptides, dermicidin and indolicidin than isolates from the epidemic clones from which they originated (Li et al., 2009). Despite these reported resistances, the immune-modulatory properties of HDPs, which may arguably be more important than their direct antimicrobial therapeutic properties, are not influenced by conventional resistance mechanisms and this is where HDPs may offer a real advantage over conventional antibiotics.
[...]
Some of these host defence mimics, in addition to their excellent drug-like properties, failed to generate resistant derivatives of S. aureus in vitro compared with ciprofloxacin or norfloxacin (Tew et al., 2006). Targeted delivery of host defence peptides to the site of infection may further improve the therapeutic potential of these molecules. The increased local concentrations that could be reached with this approach could potentially remove constraints because of higher relative MICs for some HDPs.
3) EXPERIMENTAL EVOLUTION OF RESISTANCE TO AN ANTIMICROBIAL PEPTIDE (2006)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560030/
INTRO: The evolution of resistance to every widely used commercial antibiotic has gone a long way toward annulling recent advances in antibacterial chemotherapy. In the past 50 years, resistance to every new antibiotic has appeared in microbial populations within a few years of its introduction (Palumbi 2001). The decline in the effectiveness of current therapies has led to a search for new kinds of agent, including antibiotics based on cationic antimicrobial peptides, which are part of the innate immune system of all multicellular organisms (Hancock et al. 1995; Andreu & Rivas 1998; Zasloff 2002; Reddy et al. 2004; Toke 2005).
CONCLUSION This study suggests that, like conventional anti-infective agents, the therapeutic use of RAMPS could result in the spread of resistant organisms. These therapeutics should be carefully and appropriately regulated to minimize emergence of resistant organisms from treated individuals and from environments in which large amounts of an anti-infective would be distributed, such as hospitals and stockyard. It is not our intention to discourage or retard the development of potentially useful antimicrobial agents. What we wish to suggest is that as we develop RAMPs for use as human and veterinary anti-infectives we also seriously consider the consequences of the emergence of resistant organisms. Will organisms that emerge resistant to a synthetic RAMP such as pexiganan also exhibit resistance to endogenous, natural antimicrobial peptides? Would these resistant organisms be more pathogenic than non-resistant strains? Could resistance against a synthetic peptide evolve in vivo, for example, in the setting of the long-term exposure of an animal? How should these concerns be translated into practice by the governmental regulatory bodies that ultimately approve new anti-infectives? Thoughtful analysis of the potential emergence of resistance against these novel anti-infective molecules before they are in widespread use will, in our opinion, help maximize their ultimate benefit to society.
4) HOST DEFENCE PEPTIDES: ANTIMICROBIAL AND IMMUNOMODULATORY ACTIVITY AND POTENTIAL APPLICATIONS FO TACKLING ANTIBIOTIC-RESISTANCE INFECTIONS (2009)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167646/
EXCERPT
Concerns have been raised that a widespread use of HDPs in the clinic would select for pathogens resistant to natural immune defences. Indeed, many bacterial species already possess modestly effective resistance mechanisms, including peptide degradation, sequestration, efflux, and chemical modifications of cell walls and membranes to reduce HDP binding;74, 75 resistance to HDPs can be selected in the laboratory.76 Nevertheless, HDPs are less prone to inducing resistance than conventional antibiotics because they often use several microbicidal mechanisms simultaneously, targeting many microbial systems with low affinity rather than having one specific target.75 Also, because of the diverse mechanisms of peptide action, the use of synthetic peptides that do not occur in nature could partly alleviate the problem of resistance to natural HDPs. Finally, immunomodulatory peptides that act on the host rather than on the pathogen offer a unique opportunity to minimise the direct selective pressures for pathogen resistance.
(longer post, be forewarned)
Thought folks might be interested in some literature/commentary that gets to the Resistance Q. Have been looking into it for a few weeks.
Below a post from a hyperbolic Polymedix fan (seems like an insider) from 2011. To Landekic's comment that their compounds hardly met a bug they couldn't kill. Whether resistance never develops as this person argued, or will just take a lot longer (my thoughts), is still an open Q. To that end, I included three other relevant cites.
One, published in 2012, covers Host Defensin Peptides (refs PMX-30063, Brilacidin) in the treatment of MRSA; the second, published in 2006, was co-written by Michael Zasloff, the Magainin/Pexiganin [Dipexium Rx's Locilex] (frog skin) discoverer out of Georgetown who expressed initial skepticism re Brilacidin. (See Manmade Defensins... article/excerpt below; have posted before.) And the third is by the Defensin-Mimetics folks out of British Columbia (Hancock).
What most caught my eye, as to the pub'd studies, is that the marshalling of host resources tied to the immune response may be more important in reducing the likelihood of resistance than the ability -- via evolutionary pressure (adaptation) -- for the bug to armor up (so to speak). Synthetic peptides may also have a distinct advantage.
MANMADE DEFENSIN RIPS APART RESISTANT BACTERIA
http://www.newscientist.com/article/dn13924-manmade-defensin-rips-resistant-bacteria-apart.html#.VLW-Y0ZHbCQ
EXCERPT
"For conventional antibiotics, you generally find it takes 100 times more of the antibiotic to kill the bacteria after 9 repeats," says Nick Landekic, Polymedix's chief executive. "We've done 14 repeats with PMX-30063 and there is no change in its potency." "Really exciting" Michael Zasloff at Georgetown University, Washington DC, US, was not involved with the work but plans to follow its progress. "Their compounds are really exciting and look great, but the value of this class will be based on safety." [AND SAFETY HAS BEEN MET] He says there is a chance that PMX-30063 may punch holes in human cells as well as bacterial ones." My concerns are with how it interacts with sites in the body known to be sensitive to damage by positively-charged peptides - areas such as the kidney and middle ear," says Zasloff. [NOPE DIDNT HAPPEN] DeGrado and colleagues think the risk is low, saying their molecule is several thousand times more likely to target bacterial cells than it is to attack mammalian ones. [AND DEGRADO WAS RIGHT]
BLOG POST: BACTERIAL RESISTANCE TO THE PMX MOLECULES
http://pymx.blogspot.com/2011/02/bacterial-resistance-to-pmx-molecules.html?m=1
Frankly, the PolyMedix PMX molecules are simply resistance proof. In order for a bacterium to gain resistance it would have to evolve an entire new plasma membrane with a bilipid structure entirely different from what it’s genetically programed to synthesize and utilize. Dr. DeGrado’s molecules are designed to spontaneously latch on to both the hydrophillic outer layer of the membrane and bore into the hydrophobic interior fatty layer. When this happens, the membrane loses integrity and rips apart. The stuff in the cell is free then to diffuse out. The bacterium is then functionally dead.
To keep any of that from happening, the bacterium must present a different membrane without its peculiar hydrophyllic and hydrophobic layers—which are unique in bacteria compared to unaffected animal (human) cell membranes.
I’ve said it before. There simply cannot be any appearance of bacterial resistance to the PMX molecules.
PolyMedix molecules have no need to get through the plasma membrane of the bacteria. They must merely touch them, and they dissolve, so to speak.
************************************
PolyMedix molecules work—kill bacteria—in ways no existing antibiotic does. Moreover, and crucially, there is no foreseeable means by which any bacterium could evolve resistance. Notice that the PolyMedix lawyers have caused all the information from the company on this point to claim, so to speak, “Resistance is thought to be unlikely...,” or words to that effect. Those of us who know a bit about bacterial genetics and the structure and function of bacterial plasma membranes, know fully that nothing can stop the PolyMedix molecules, regardless.
The seminal phrase (and mechanism) for PMX efficacy is “membrane disruption.” No other antibiotic works this way. Penicillin, and all the rest, have to get themselves inserted inside the bacterium, where they bind on to, or otherwise disrupt crucial molecules, often essential enzymes. The PMX stuff all works from the outside, so no problems getting in.
And this is an important point, too. You mentioned that it took thousands of years for conventional resistance to occur. That’s probably not the case. Most antibiotics originated from naturally occurring molecules, often in soil. They have been confronting bacteria for millennia, and the bacteria already have genes, if expressed, that can fight them off—which they are now doing in MRSA and other resistant bacteria.
Innate, unexpressed resistance to PMX molecules will not exist. PolyMedix molecules are unique. They have on their surfaces a bunch of molecular “sticky points” and adjacent “repellant points” that when bumped against a bacterium, while merely floating around in blood, cause the bacterium’s plasma membrane to spontaneously break apart, the so-called “membrane disruption.” The PMX molecules are little armor-piercing devices that repeatedly poke holes in the bacteria, because of the unique chemistry of bacteria plasma membranes. The bacteria have no way to repair such rapid, almost instantaneous damage, nor do they have any way of making a functioning plasma membrane that does not have the “sticky spots.” It’s no-win for the germs. Period.
Another Post of his worth a look--Polymedix -vs- Tetraphase
http://pymx.blogspot.com/2011/02/posts-from-falconer66a-polymedix-vs.html?m=1
2) BEYOND CONVENTIONAL ANTIBIOTICS FOR THE FUTURE TREATMENT OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS INFECTIONS: TWO NOVEL ALTERNATIVES (2012)
http://femsim.oxfordjournals.org/content/65/3/399.long
EXCERPTS
The investigation of alternative therapeutic agents with novel mechanisms of action remains largely an activity for academic researchers and small biotechnology companies. This type of research has resulted in preclinical developments in the areas of innate immune defence peptides and antipathogenic agents with potential as novel anti-MRSA therapeutics. For example, cationic peptides offer multiple and alternative modes of action that may circumvent the problem of antimicrobial resistance. Significant improvements, to the chemistry of such peptides, have increased their attractiveness in terms of pharmacokinetics, toxicity and cost.
[...]
A nonpeptide structural mimetic of defensin, with low toxicity, PMX-30063D, is currently in clinical development for infections involving S. aureus.
[...]
It has been suggested that HDPs, if developed as MRSA anti-infectives, would have low propensity to select resistant mutants compared with classical antibiotics. This is based on the multiple mechanisms of action of HDPs. However, bacteria and the human host have co-evolved, and S. aureus adaptations have been described for a small number of host defence peptides. For example, reduced susceptibility to defensin and protegrins has been demonstrated in S. aureus which is mediated by the incorporation of positively charged l-lysine into the cytoplasmic membrane and is catalysed by the product of the mprF gene (Peschel et al., 2001; Ernst et al., 2009). Interestingly, this membrane modification also contributes to S. aureus resistance to the CAMP-like agent daptomycin, which is currently in clinical use for MRSA infections. An investigation of the evolution of CA-MRSA shows that USA 300 and USA500 strains are more resistant to the innate immune defence peptides, dermicidin and indolicidin than isolates from the epidemic clones from which they originated (Li et al., 2009). Despite these reported resistances, the immune-modulatory properties of HDPs, which may arguably be more important than their direct antimicrobial therapeutic properties, are not influenced by conventional resistance mechanisms and this is where HDPs may offer a real advantage over conventional antibiotics.
[...]
Some of these host defence mimics, in addition to their excellent drug-like properties, failed to generate resistant derivatives of S. aureus in vitro compared with ciprofloxacin or norfloxacin (Tew et al., 2006). Targeted delivery of host defence peptides to the site of infection may further improve the therapeutic potential of these molecules. The increased local concentrations that could be reached with this approach could potentially remove constraints because of higher relative MICs for some HDPs.
3) EXPERIMENTAL EVOLUTION OF RESISTANCE TO AN ANTIMICROBIAL PEPTIDE (2006)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560030/
INTRO: The evolution of resistance to every widely used commercial antibiotic has gone a long way toward annulling recent advances in antibacterial chemotherapy. In the past 50 years, resistance to every new antibiotic has appeared in microbial populations within a few years of its introduction (Palumbi 2001). The decline in the effectiveness of current therapies has led to a search for new kinds of agent, including antibiotics based on cationic antimicrobial peptides, which are part of the innate immune system of all multicellular organisms (Hancock et al. 1995; Andreu & Rivas 1998; Zasloff 2002; Reddy et al. 2004; Toke 2005).
CONCLUSION This study suggests that, like conventional anti-infective agents, the therapeutic use of RAMPS could result in the spread of resistant organisms. These therapeutics should be carefully and appropriately regulated to minimize emergence of resistant organisms from treated individuals and from environments in which large amounts of an anti-infective would be distributed, such as hospitals and stockyard. It is not our intention to discourage or retard the development of potentially useful antimicrobial agents. What we wish to suggest is that as we develop RAMPs for use as human and veterinary anti-infectives we also seriously consider the consequences of the emergence of resistant organisms. Will organisms that emerge resistant to a synthetic RAMP such as pexiganan also exhibit resistance to endogenous, natural antimicrobial peptides? Would these resistant organisms be more pathogenic than non-resistant strains? Could resistance against a synthetic peptide evolve in vivo, for example, in the setting of the long-term exposure of an animal? How should these concerns be translated into practice by the governmental regulatory bodies that ultimately approve new anti-infectives? Thoughtful analysis of the potential emergence of resistance against these novel anti-infective molecules before they are in widespread use will, in our opinion, help maximize their ultimate benefit to society.
4) HOST DEFENCE PEPTIDES: ANTIMICROBIAL AND IMMUNOMODULATORY ACTIVITY AND POTENTIAL APPLICATIONS FO TACKLING ANTIBIOTIC-RESISTANCE INFECTIONS (2009)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167646/
EXCERPT
Concerns have been raised that a widespread use of HDPs in the clinic would select for pathogens resistant to natural immune defences. Indeed, many bacterial species already possess modestly effective resistance mechanisms, including peptide degradation, sequestration, efflux, and chemical modifications of cell walls and membranes to reduce HDP binding;74, 75 resistance to HDPs can be selected in the laboratory.76 Nevertheless, HDPs are less prone to inducing resistance than conventional antibiotics because they often use several microbicidal mechanisms simultaneously, targeting many microbial systems with low affinity rather than having one specific target.75 Also, because of the diverse mechanisms of peptide action, the use of synthetic peptides that do not occur in nature could partly alleviate the problem of resistance to natural HDPs. Finally, immunomodulatory peptides that act on the host rather than on the pathogen offer a unique opportunity to minimise the direct selective pressures for pathogen resistance.
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