A large series of publications1-9 has proposed that cationic peptides from leukocytes kill bacteria primarily by causing a depolarization of their membranes leading to enhanced permeability. One group of cationic peptides from human neutrophils was even coined bactericidal/permeability-increasing proteins.3Surprisingly, however, none of a large series of other publications that had proposed a concept that cationic agents from neutrophils might be bactericidal also by virtue of their capacity to activate the bacterial autolytic wall enzymes (muramidases), leading to bacteriolysis and cell death,10-22 has ever been cited in any of the publications by the leading authors in this field of research.1-9 

For the information of your readers, there exist a series of 16 publications since 1974 entitled “Effect of leukocyte hydrolases on bacteria” and several additional publications on the same subject under different titles, many of them published in journals covered by Medline; the references contain a selected list of these.10-22,24 These had proposed that many of the highly cationic agents either present in plasma or generated by activated phagocytes (eg, lysozymes, PLA2, elastase, cathepsin G, myeloperoxidase, bactericidal/permeability-increasing proteins, defensins, etc) might kill bacteria not simply by acting on the membranes to cause depolarization and enhanced permeability1-7 but also by an indirect mechanism. This involves a deregulation, by the cationic agents, of the anionic and amphiphilic regulators of the autolytic wall enzymes(muramidases) (lipoteichoic acid in Gram-positives and Forssman antigens in Gram-negatives)16,17,23-25 resulting in hydrolysis of the peptidoglycan, in bacteriolysis, and in cell death. It is of great clinical importance that the bacteriolysis-inducing activity of cationic agents mimics that of beta-lactam antibiotics.26 Furthermore, the observations that a variety of highly negatively charged, sulfated anionic agents can act as potent inhibitors of the cationic agent– and beta-lactam–induced bacteriolysis11,12,14,16,17,27-30further stress the importance of the autolytic systems in bacterial killing. This phenomenon might also be of great clinical significance especially in selecting measures to control postinfectious sequelae that undoubtedly are triggered by the release of bacterial components, especially following bacteriolysis.

Regrettably, attempts to bring these issues to the awareness of the leading investigators in the field of cationic proteins1-9and of clinicians involved is the clinical aspects of sepsis control have not been successful.

If the concept that cationic agents might be bactericidal also because of their bacteriolysis-inducing properties is reasonable and scientifically sound, it is expected that publications describing this phenomenon should be cited by authors studying the bactericidal effects of cationic agents. If on the other hand one deems that this concept is for some reason erroneous, nonsensical, and scientifically unacceptable, such publications should definitely be cited but properly discussed, challenged, and even also ridiculed. But it is totally unacceptable and unreasonable that such publications be simply ignored!

Unfortunately, the avoidance of relevant citations and the disregard for concepts that might perhaps not “fit” current dogma and beliefs have reached epidemic levels. This is how pioneering publications proposing “novel approaches and ideas”16,17,29,30 to explain additional mechanisms of microbial killing might be lost forever. More importantly, these concepts will probably never reach the attention of clinicians interested in the pathogenesis of inflammation, infection, postinfectious sequelae, and the mechanisms of host defense.29-31 

But what is even more disturbing, concerning, and unacceptable is that the expert referees selected by the editorial boards of journals and who should have been knowledgeable of the relevant literature failed to alert the authors to the existence of key publications on bacteriolysis so relevant to the subject of the papers and of the reviews they had been assigned to judge.

Am I wrong to assume that the task of a journal's editorial board is to ensure that all viewpoints and ideas, both “conventional” and nonconventional, be equally represented? Excuses either that limitations to the number of references permissible were the reason for not citing basic and pioneering publications or that the authors had been “instructed” to discuss only a narrow field of research and to disregard others fields with direct relevance are unacceptable.

A failure to give credit to relevant papers is also unacademic, self-defeating, unethical, and therefore unacceptable by all standards. Furthermore, are papers older than 15 years, or so, already passéand, therefore, unworthy of being acknowledged?

References

References
1
Levy
O
Antibiotic proteins of polymorphonuclear leukocytes.
Eur J Hematol.
56
1996
263
277
2
Levy
O
Antimicrobial proteins and peptides of blood: template for novel anti-microbial agents.
Blood.
96
2000
2664
2672
3
Elsbach
P
The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense.
J Leukoc Biol.
64
1998
14
18
4
Elsbach
P
Weiss
G
Oxygen-independent antimicrobial systems of phagocytes.
Inflammation: Basic Principles and Clinical Correlates.
Gallin
JI
Goldstein
IM
Snyderman
R
1992
603
636
Raven Press
New York, NY
5
Elsbach
P
Weiss
G
Levy
O
Oxygen-independent antimicrobial systems of phagocytes.
Inflammation: Basic Principles and Clinical Correlates.
3rd edition.
Gallin
JI
Snyderman
R
1999
801
818
Raven Press
New York, NY
6
Ganz
T
Lehrer
RI
Antimicobial peptides from higher eukaryotes: biology and application.
Mol Med Today.
5
1999
292
297
7
Ganz
T
Lehrer
RI
Antimicrobial peptides of leukocytes.
Curr Opin Hematol.
4
1997
53
58
8
Hancock
R
Antibacterial peptides and outer membranes of Gram-negative bacilli.
J Med Microbiol.
46
1997
1
3
9
Hancock
R
Chapple
D
Peptide antibiotics.
Antimicrob Agents Chemother.
43
1999
1217
1323
10
Neeman
N
Lahav
M
Ginsburg
I
The effect of leukocyte hydrolases on bacteria, II: the synergistic action of lysozyme and extracts of PMNs, macrophages, lymphocytes and platelets in bacteriolysis.
Proc Soc Exp Biol Med.
146
1974
1137
1145
11
Lahav
M
Ne'eman
N
James
J
Ginsburg
I
The effect of leukocyte hydrolases on bacteria, III: bacteriolysis induced by extracts of different leukocyte populations and the inhibition of lysis by macromolecular substances.
J Infect Dis.
131
1975
149
157
12
Ginsburg
I
Lahav
M
Ne'eman
N
Duchan
Z
Chanes
S
Sela
MN
The interaction of leukocytes and their hydrolases with bacteria in vitro and in vivo: the modification of the bactericidal and bacteriolytic reactions by cationic and anionic macromolecular substances and by anti-inflammatory agents.
Agents and Actions.
6
1976
292
305
13
Lahav
M
Ne'eman
N
Sela
MN
et al. 
Effect of leukocyte hydrolases on bacteria, XIII: role played by leukocyte extracts, lysolecithin, phospholipase A2, lysozyme, cationic proteins and detergents in the solubilization of lipids from Staphylococcus aureus and group A streptococci: relation to bactericidal and bacteriolytic reactions.
Inflamm.
3
1979
365
377
14
Ginsburg
I
Lahav
M
Giesbrecht
P
et al. 
The effect of leukocyte hydrolases on bacteria, XVI: activation by leukocyte factors and cationic substances of autolytic enzymes in Staphylococcus aureus: modulation by anionic polyelectrolytes in relation to the survival of bacteria in inflammatory exudates.
Inflamm.
6
1982
269
284
15
Wecke
J
Lahav
M
Ginsburg
I
et al. 
Cell wall degradation of Staphylococcus aureus by lysozyme.
Arch Microbiol.
131
1982
116
123
16
Ginsburg
I
Cationic polyelectrolytes: a new look at their role as opsonins, as stimulators of the respiratory burst in leukocytes in bacteriolysis and as modulators of immune complex disease.
Inflamm.
11
1987
137
142
17
Ginsburg
I
The biochemistry of bacteriolysis: facts, paradoxes and myths.
Microbiol Sci.
5
1988
137
142
18
Sahl
HG
Bactericidal cationic peptides involved in bacterial antagonism and host defense.
Microbiol Sci.
2
1985
212
217
19
Laible
NJ
Germaine
GR
Bactericidal activity of human lysozyme, muramidase-inactive lysozyme, and cationic polypeptides against Streptococcus sanguis and Streptococcus faecalis: inhibition by chitin oligosaccharides.
Infect Immun.
48
1985
720
728
20
Cottagnoud
P
Tomasz
A
Triggering of pneumococcal autolysis by lysozyme.
J Infect Dis.
167
1993
685
690
21
Galvez
A
Valdivia
E
Martinez-Bueno
M
Maqueda
M
Induction of autolysis in Entercoccus faecalis S-47 by peptide AS-48.
J Appl Bacteriol.
69
1990
406
413
22
Bierbaum
G
Sahl
HG
Influence of cationic peptides on the activity of autolytic endo acetylmuramidase of Staphylococcus simulans 22.
FEMS Microbiol Lett.
58
1988
223
228
23
Holtje
JV
Tomasz
A
Lipoteichoic acid: a specific inhibitor of autolysin activity in pneumococci.
Proc Natl Acad Sci U S A.
72
1975
1690
1694
24
Ginsburg
I
Lahav
M
Lysis and biodegradation of microorganisms in infectious sites may involve cooperation among leukocyte, serum factors and bacterial wall autolysins.
Eur J Microbiol.
2
1982
186
191
25
Cleveland
RF
Daneo-Moore
L
Wicken
AJ
Shockman
GD
Effect of lipoteichoic acid and lipids on lysis of Streptococcus faecalis.
J Bacteriol.
127
1999
1582
1584
26
Tomasz
A
Waks
S
Mechanisms of action of penicillin: triggering of pneumococcal autolytic enzymes by inhibitor of cell wall synthesis.
Proc Natl Acad Sci U S A.
72
1975
416
462
27
Wecke
J
Lahav
M
Ginsburg
I
Kwa
E
Giesbrecht
P
Inhibition of wall autolysis of Staphylococcus aureus by polyanethole sulfonate.
Arch Microbiol.
144
1986
110
115
28
Wecke
J
Kwa
E
Lahav
M
Ginsburg
I
Giesbrecht
P
Suppression of penicillin-induced bacteriolysis by some anticoagulants.
J Antimicrobial Chemother.
20
1987
47
55
29
Ginsburg
I
Multidrug strategies are necessary to inhibit the synergistic mechanisms causing tissue damage and organ failure in post-infectious sequelae.
Inflammopharmacol.
7
1999
207
217
30
Ginsburg
I
Is a failure to inhibit bacteriolysis and the synergy among microbial and host-derived agonists the main reason for tissue damage in post-infectious sequelae?
Inflamm.
25
2001
1
10
31
Ginburg I. The Biochemical basis of bacteriolysis and its role in the pathophysiology of inflammation and post-infectious sequelae. APMIS. In press.