Bactericidal cationic peptides can also function as bacteriolysis-inducing agents mimicking beta-lactam antibiotics?; it is enigmatic why this concept is consistently disregarded

Ginsburg, Isaac

doi:10.1016/j.mehy.2003.11.017

Cited by 50 publications

(36 citation statements)

References 71 publications

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“…Using two synthesized LLP, we have confirmed that LLP can be more bactericidal to pneumococci than apo-hLf (22). It has been proposed that these antibacterial peptides act at or through the bacterial membrane (1,4,16,27).…”

Section: Discussionmentioning

confidence: 55%

Serine Protease PrtA from Streptococcus pneumoniae Plays a Role in the Killing of S. pneumoniae by Apolactoferrin

et al. 2011

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It is known that apolactoferrin, the iron-free form of human lactoferrin, can kill many species of bacteria, including Streptococcus pneumoniae. Lactoferricin, an N-terminal peptide of apolactoferrin, and fragments of it are even more bactericidal than apolactoferrin. In this study we found that apolactoferrin must be cleaved by a serine protease in order for it to kill pneumococci. The serine protease inhibitors were able to block killing by apolactoferrin but did not block killing by a lactoferrin-derived peptide. Thus, the killing of pneumococci by apolactoferrin appears to require a protease to release a lactoferricin-like peptide(s). Incubation of apolactoferrin with growing pneumococci resulted in a 12-kDa reduction in its molecular mass, of which about 7 to 8 kDa of the reduction was protease dependent. Capsular type 2 and 19F strains with mutations in the gene encoding the major cell wall-associated serine protease, prtA, lost much of their ability to degrade apolactoferrin and were relatively resistant to killing by apolactoferrin (P < 0.001). Recombinant PrtA was also able to cleave apolactoferrin, reducing its mass by about 8 kDa, and greatly enhance the killing activity of the solution containing the apolactoferrin and its cleavage products. Mass spectroscopy revealed that PrtA makes a major cut between amino acids 78 and 79 of human lactoferrin, removing the N-terminal end of the molecule (about 8.6 kDa). The simplest interpretation of these data is that the mechanism by which apolactoferrin kills Streptococcus pneumoniae requires the release of a lactoferricin-like peptide(s) and that it is this peptide(s), and not the intact apolactoferrin, which kills pneumococci.Streptococcus pneumoniae is a major inhabitant of the human upper respiratory tract and can cause pneumonia, sepsis, meningitis, and otitis media (21a). Pneumococci are common inhabitants of the nasopharynx of healthy children and adults. Pneumococci can cause serious disease when they leave the nasopharynx and successfully invade the middle ear, lungs, blood, or brain (21a). Although specific antibody can mediate protection against pneumococcal infection (14, 53), there is also evidence that antibody is not necessary for immunity to colonization and that innate immunity plays a significant role (30,50,58). Moreover, the molecular mechanisms involved in the interaction of S. pneumoniae with the innate immune system are incompletely understood.Known innate immune system components that protect against bacterial infection in the upper airways include mucus flow, antibacterial proteins, such as lysozyme and lactoferrin, and antibacterial peptides, such as ␣-defensins and ␤-defensins (57). Human lactoferrin (hLf) has been reported to play a number of different roles in mammals, including immunoregulation, iron sequestration, promotion of calcium uptake, and bactericidal activity (52). The observation that pneumococcal surface protein A (PspA) specifically inhibits in vitro killing of pneumococci by apolactoferrin (apo-hLf), the iron-free for...

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Section: Discussionmentioning

confidence: 55%

Serine Protease PrtA from Streptococcus pneumoniae Plays a Role in the Killing of S. pneumoniae by Apolactoferrin

et al. 2011

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“…The Holy Grail of all drug development platforms is finding a novel biopolymer target, specific for the given disease, in our case for bacterial survival, virulence or toxicity. In that regard, newly discovered activities of AMP include inhibition of RNA [19] or protein synthesis [20], attenuation of protein folding [21] or lipid complexation [22], and activation of microbial autolytic systems [23] or deactivation of bacterial toxins [24]. While these activities can explain some positive in vivo results that bacterial membrane disintegration cannot, they are unable to account for the success of many systemic and local infection treatments in the absence of in vitro killing of bacteria or inactivating the newly recognized target proteins.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory effects of anti-microbial peptides

Ötvös¹

2016

Acta Microbiologica et Immunologica Hungarica

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Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro-and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

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“…Apparently many AMPs interfere with bacterial enzymatic processes (31). One hypothesis is that in addition to membrane activities, cationic peptides and proteins might render bacteria nonviable by activating their autolytic wall enzymes, muramidases, resulting in bacteriolysis (14). In this respect cationic AMPs mimic the bactericidal effects exerted by ␤-lactam antibiotics.…”

mentioning

confidence: 99%

Dermcidin-Derived Peptides Show a Different Mode of Action than the Cathelicidin LL-37 against Staphylococcus aureus

Senyürek

Paulmann

Sinnberg

et al. 2009

Antimicrob Agents Chemother

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Dermcidin (DCD) is an antimicrobial peptide which is constitutively expressed in eccrine sweat glands. By postsecretory proteolytic processing in sweat, the DCD protein gives rise to anionic and cationic DCD peptides with a broad spectrum of antimicrobial activity. Many antimicrobial peptides induce membrane permeabilization as part of their killing mechanism, which is accompanied by a loss of the bacterial membrane potential. In this study we show that there is a time-dependent bactericidal activity of anionic and cationic DCD-derived peptides which is followed by bacterial membrane depolarization. However, DCD-derived peptides do not induce pore formation in the membranes of gram-negative and gram-positive bacteria. This is in contrast to the mode of action of the cathelicidin LL-37. Interestingly, LL-37 as well as DCD-derived peptides inhibit bacterial macromolecular synthesis, especially RNA and protein synthesis, without binding to microbial DNA or RNA. Binding studies with components of the cell envelope of gram-positive and gram-negative bacteria and with model membranes indicated that DCD-derived peptides bind to the bacterial envelope but show only a weak binding to lipopolysaccharide (LPS) from gram-negative bacteria or to peptidoglycan, lipoteichoic acid, and wall teichoic acid, isolated from Staphylococcus aureus. In contrast, LL-37 binds strongly in a dosedependent fashion to these components. Altogether, these data indicate that the mode of action of DCD-derived peptides is different from that of the cathelicidin LL-37 and that components of the bacterial cell envelope play a role in the antimicrobial activity of DCD.

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Bactericidal cationic peptides can also function as bacteriolysis-inducing agents mimicking beta-lactam antibiotics?; it is enigmatic why this concept is consistently disregarded

Cited by 50 publications

References 71 publications

Serine Protease PrtA from Streptococcus pneumoniae Plays a Role in the Killing of S. pneumoniae by Apolactoferrin

Serine Protease PrtA from Streptococcus pneumoniae Plays a Role in the Killing of S. pneumoniae by Apolactoferrin

Immunomodulatory effects of anti-microbial peptides

Dermcidin-Derived Peptides Show a Different Mode of Action than the Cathelicidin LL-37 against Staphylococcus aureus

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