Table Info

Table 1.

Effect of Lf on bacterial virulence factors

Virulence factor	Lf	Pathogen	Effect	Ref.
LPS	hLf	E. coli K. pneumoniae P. aeruginosa	Decreases endotoxicity by binding to LPS.	[30]
	hLf bLf Lfcin	E. coli S. typhimurium	Releases LPS and alters outer membrane (OM) permeability.	[31, 32]
	hLf	E. coli	Destabilizes OM by binding to LPS.	[33]
Secretion systems	hLf	Shigella E. coli EPEC	Degradation of proteins associated to the type III secretion system.	[35]
Secretion systems	rLf	H. pylori	Decreases expression of the oncogenic cag pathogenicity island-encoded type IV secretion system.	[56]
Protease secretion	hLf	H. influenzae	Cleavage within the helper region of IgA (IgAβ) domain.	[38]
	bLf	P. gingivalis	Inhibits the activity of the cysteine proteases.	[39]
	bLf	A. pleuroneumoniae	Inhibits activity of metalloproteases.	[22]
	bLf	M. haemolytica	Inhibits secretion and activity of cysteine and metalloproteases.	[40, 57]
Adhesion	hLf	E. coli EPEC	Inhibits adhesion to HeLa cells.	[41]
	bLf bLf polypeptides	S. mutans	Inhibits adhesion to saliva-coated hydroxyapatite.	[42]
	bLf rhLf	S. gordonii	Inhibits attachment to glass disks. Inhibits adhesion to titanium surfaces.	[43] [44]
Adhesion and biofilm formation	rhLf bLfcinB	B. fragilis B. thethaiotaomicron	Inhibits binding to laminin and biofilm formation.	[46]
	hLf	S. agalactiae	Inhibits adherence to human gestational membranes and biofilm formation.	[47, 48]
	hLf peptide	S. sanguinis	Inhibits adhesion to titanium surfaces and reduces early stages of biofilm formation.	[49]
Biofilm formation	bLf	P. aeruginosa	Inhibits biofilm formation and reduces preformed biofilm.	[50]
	bLfcin bLfampin bLfchimera	P. aeruginosa	Decreases biofilm formation.	[51]
	bLf hLf	P. gingivalis P. intermedia	Abolishes biofilm formation and reduces preformed biofilm.	[39, 52]
	hLf bLf	A. baumanii	Inhibits biofilm formation.	[53]
	bLf	E. coli EAEC	Decreases biofilm formation.	[54]
	bLf	S. pneumoniae	Eradicates form biofilm and disrupts eDNA.	[55]

Lf: lactoferrin; LPS: lipopolysaccharides; hLf: human Lf; bLf: bovine Lf; Lfcin: lactoferricin; rLf: recombinant Lf; EPEC: enteropathogenic E. coli; rhLf: recombinant human Lf; bLfcinB: bovine Lfcin B; bLfcin: bovine Lfcin; bLfampin: bovine lactoferrampin; bLfchimera: bovine Lf chimera; EAEC: enteroaggregative E. coli; A. baumanii: Acinetobacter baumannii; A. pleuroneumoniae: Actinobacillus pleuropneumoniae; B. fragilis: Bacteroides fragilis; B. thethaiotaomicron: Bacteroides thetaiotaomicron; E. coli: Escherichia coli; H. influenza: Haemophilus influenza; H. pylori: Helicobacter pylori; K. pneumoniae: Klebsiella pneumoniae; M. haemolytica: Mannheimia haemolytica; P. aeruginosa: Pseudomonas aeruginosa; P. gingivalis: Porphyromonas gingivalis; S. agalactiae: Streptococcus agalactiae; S. gordonii: Streptococcus gordonii; S. mutans: Streptococcus mutans; S. pneumoniae: Streptococcus pneumoniae; S. sanguinis: Streptococcus sanguinis; S. typhimurium: Salmonella typhimurium

Declarations

Author contributions

GRR and LRM: Conceptualization, Investigation, Project administration, Supervision, Visualization, Writing—original draft, Writing—review & editing. MdlG: Conceptualization, Supervision, Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Adebisi YA, Ogunkola IO. The global antimicrobial resistance response effort must not exclude marginalised populations. Trop Med Health. 2023;51:33. [DOI] [PubMed] [PMC]

Catalano A, Iacopetta D, Ceramella J, Scumaci D, Giuzio F, Saturnino C, et al. Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies. Molecules. 2022;27:616. [DOI] [PubMed] [PMC]

Eisenreich W, Rudel T, Heesemann J, Goebel W. Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens. Front Cell Infect Microbiol. 2022;12:900848. [DOI] [PubMed] [PMC]

Bukowska-Ośko I, Popiel M, Kowalczyk P. The Immunological Role of the Placenta in SARS-CoV-2 Infection-Viral Transmission, Immune Regulation, and Lactoferrin Activity. Int J Mol Sci. 2021;22:5799. [DOI] [PubMed] [PMC]

Wang RJ, Li JQ, Chen Y, Zhang LX, Xiao LH. Widespread occurrence of Cryptosporidium infections in patients with HIV/AIDS: Epidemiology, clinical feature, diagnosis, and therapy. Acta Trop. 2018;187:257–63. [DOI] [PubMed]

Drago-Serrano ME, de la Garza-Amaya M, Luna JS, Campos-Rodríguez R. Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects. Int Immunopharmacol. 2012;12:1–9. [DOI] [PubMed]

Baker HM, Baker EN. A structural perspective on lactoferrin function. Biochem Cell Biol. 2012;90:320–8. [DOI] [PubMed]

Legrand D, Pierce A, Elass E, Carpentier M, Mariller C, Mazurier J. Lactoferrin structure and functions. Adv Exp Med Biol. 2008;606:163–94. [DOI] [PubMed]

Karav S, German JB, Rouquié C, Le Parc A, Barile D. Studying Lactoferrin N-Glycosylation. Int J Mol Sci. 2017;18:870. [DOI] [PubMed] [PMC]

10.

Anderson BF, Baker HM, Dodson EJ, Norris GE, Rumball SV, Waters JM, et al. Structure of human lactoferrin at 3.2-A resolution. Proc Natl Acad Sci U S A. 1987;84:1769–73. [DOI] [PubMed] [PMC]

11.

Moore SA, Anderson BF, Groom CR, Haridas M, Baker EN. Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution. J Mol Biol. 1997;274:222–36. [DOI] [PubMed]

12.

Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, et al. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003;47:607–17. [DOI] [PubMed]

13.

Ptaszyńska N, Olkiewicz K, Okońska J, Gucwa K, Łęgowska A, Gitlin-Domagalska A, et al. Peptide conjugates of lactoferricin analogues and antimicrobials-Design, chemical synthesis, and evaluation of antimicrobial activity and mammalian cytotoxicity. Peptides. 2019;117:170079. [DOI] [PubMed]

14.

Bruni N, Capucchio MT, Biasibetti E, Pessione E, Cirrincione S, Giraudo L, et al. Antimicrobial Activity of Lactoferrin-Related Peptides and Applications in Human and Veterinary Medicine. Molecules. 2016;21:752. [DOI] [PubMed] [PMC]

15.

Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M. Identification of the bactericidal domain of lactoferrin. Biochim Biophys Acta. 1992;1121:130–6. [DOI] [PubMed]

16.

Haney EF, Nazmi K, Bolscher JGM, Vogel HJ. Structural and biophysical characterization of an antimicrobial peptide chimera comprised of lactoferricin and lactoferrampin. Biochim Biophys Acta. 2012;1818:762–75. [DOI] [PubMed]

17.

Drago-Serrano ME, Campos-Rodríguez R, Carrero JC, de la Garza M. Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Int J Mol Sci. 2017;18:501. [DOI] [PubMed] [PMC]

18.

Zarzosa-Moreno D, Avalos-Gómez C, Ramírez-Texcalco LS, Torres-López E, Ramírez-Mondragón R, Hernández-Ramírez JO, et al. Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens. Molecules. 2020;25:5763. [DOI] [PubMed] [PMC]

19.

Avalos-Gómez C, Ramírez-Rico G, Ruiz-Mazón L, Sicairos NL, Serrano-Luna J, de la Garza M. Lactoferrin: An Effective Weapon in the Battle Against Bacterial Infections. Curr Pharm Des. 2022;28:3243–60. [DOI] [PubMed]

20.

Ashraf MF, Zubair D, Bashir MN, Alagawany M, Ahmed S, Shah QA, et al. Nutraceutical and Health-Promoting Potential of Lactoferrin, an Iron-Binding Protein in Human and Animal: Current Knowledge. Biol Trace Elem Res. 2024;202:56–72. [DOI] [PubMed] [PMC]

21.

Kowalczyk P, Kaczyńska K, Kleczkowska P, Bukowska-Ośko I, Kramkowski K, Sulejczak D. The Lactoferrin Phenomenon-A Miracle Molecule. Molecules. 2022;27:2941. [DOI] [PubMed] [PMC]

22.

Luna-Castro S, Aguilar-Romero F, Samaniego-Barrón L, Godínez-Vargas D, de la Garza M. Effect of bovine apo-lactoferrin on the growth and virulence of Actinobacillus pleuropneumoniae. Biometals. 2014;27:891–903. [DOI] [PubMed]

23.

Ulvatne H, Haukland HH, Olsvik O, Vorland LH. Lactoferricin B causes depolarization of the cytoplasmic membrane of Escherichia coli ATCC 25922 and fusion of negatively charged liposomes. FEBS Lett. 2001;492:62–5. [DOI] [PubMed]

24.

Liu Y, Han F, Xie Y, Wang Y. Comparative antimicrobial activity and mechanism of action of bovine lactoferricin-derived synthetic peptides. Biometals. 2011;24:1069–78. [DOI] [PubMed]

25.

Al-Mogbel MS, Menezes GA, Elabbasy MT, Alkhulaifi MM, Hossain A, Khan MA. Effect of Synergistic Action of Bovine Lactoferrin with Antibiotics on Drug Resistant Bacterial Pathogens. Medicina (Kaunas). 2021;57:343. [DOI] [PubMed] [PMC]

26.

Morici P, Florio W, Rizzato C, Ghelardi E, Tavanti A, Rossolini GM, et al. Synergistic activity of synthetic N-terminal peptide of human lactoferrin in combination with various antibiotics against carbapenem-resistant Klebsiella pneumoniae strains. Eur J Clin Microbiol Infect Dis. 2017;36:1739–48. [DOI] [PubMed]

27.

Gajda-Morszewski P, Brindell M. Lactoferrin as a Potent Natural Supplement Exhibiting a Synergistic Effect with Drugs in Antimicrobial and Anticancer Therapies. Curr Protein Pept Sci. 2021;22:629–40. [DOI] [PubMed]

28.

Leitão JH. Microbial Virulence Factors. Int J Mol Sci. 2020;21:5320. [DOI] [PubMed] [PMC]

29.

Farhana A, Khan YS. Biochemistry, Lipopolysaccharide. Treasure Island (FL): StatPearls Publishing; 2024. [PubMed]

30.

Appelmelk BJ, An YQ, Geerts M, Thijs BG, de Boer HA, MacLaren DM, et al. Lactoferrin is a lipid A-binding protein. Infect Immun. 1994;62:2628–32. [DOI] [PubMed] [PMC]

31.

Ellison RT 3rd, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin. Infect Immun. 1988;56:2774–81. [DOI] [PubMed] [PMC]

32.

Yamauchi K, Tomita M, Giehl TJ, Ellison RT 3rd. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect Immun. 1993;61:719–28. [DOI] [PubMed] [PMC]

33.

Chapple DS, Hussain R, Joannou CL, Hancock RE, Odell E, Evans RW, et al. Structure and association of human lactoferrin peptides with Escherichia coli lipopolysaccharide. Antimicrob Agents Chemother. 2004;48:2190–8. [DOI] [PubMed] [PMC]

34.

Green ER, Mecsas J. Bacterial Secretion Systems: An Overview. Microbiol Spectr. 2016;4:10.1128/microbiolspec.vmbf–0012. [DOI] [PubMed] [PMC]

35.

Ochoa TJ, Clearly TG. Lactoferrin disruption of bacterial type III secretion systems. Biometals. 2004;17:257–60. [DOI] [PubMed]

36.

Paredes JL, Sparks H, White AC Jr, Martinez-Traverso G, Ochoa T, Castellanos-González A. Killing of Cryptosporidium sporozoites by Lactoferrin. Am J Trop Med Hyg. 2017;97:774–6. [DOI] [PubMed] [PMC]

37.

Sundar S, Piramanayagam S, Natarajan J. A comprehensive review on human disease-causing bacterial proteases and their impeding agents. Arch Microbiol. 2023;205:276. [DOI] [PubMed]

38.

Plaut AG, Qiu J, St Geme JW 3rd. Human lactoferrin proteolytic activity: analysis of the cleaved region in the IgA protease of Haemophilus influenzae. Vaccine. 2000;19 Suppl 1:S148–52. [DOI] [PubMed]

39.

Dashper SG, Pan Y, Veith PD, Chen YY, Toh EC, Liu SW, et al. Lactoferrin inhibits Porphyromonas gingivalis proteinases and has sustained biofilm inhibitory activity. Antimicrob Agents Chemother. 2012;56:1548–56. [DOI] [PubMed] [PMC]

40.

Ramírez-Rico G, Martinez-Castillo M, Avalos-Gómez C, de la Garza M. Bovine apo-lactoferrin affects the secretion of proteases in Mannheimia haemolytica A2. Access Microbiol. 2021;3:000269. [DOI] [PubMed] [PMC]

41.

de Araújo AN, Giugliano LG. Lactoferrin and free secretory component of human milk inhibit the adhesion of enteropathogenic Escherichia coli to HeLa cells. BMC Microbiol. 2001;1:25. [DOI] [PubMed] [PMC]

42.

Oho T, Mitoma M, Koga T. Functional domain of bovine milk lactoferrin which inhibits the adherence of Streptococcus mutans cells to a salivary film. Infect Immun. 2002;70:5279–82. [DOI] [PubMed] [PMC]

43.

Arslan SY, Leung KP, Wu CD. The effect of lactoferrin on oral bacterial attachment. Oral Microbiol Immunol. 2009;24:411–6. [DOI] [PubMed]

44.

Nagano-Takebe F, Miyakawa H, Nakazawa F, Endo K. Inhibition of initial bacterial adhesion on titanium surfaces by lactoferrin coating. Biointerphases. 2014;9:029006. [DOI] [PubMed]

45.

Yin W, Wang Y, Liu L, He J. Biofilms: The Microbial “Protective Clothing” in Extreme Environments. Int J Mol Sci. 2019;20:3423. [DOI] [PubMed] [PMC]

46.

de Sá Almeida JS, de Sá Almeida JS, Teixeira FL, Boente RF, Domingues RMCP, de Paula GR, et al. Lactoferrin and lactoferricin B reduce adhesion and biofilm formation in the intestinal symbionts Bacteroides fragilis and Bacteroides thetaiotaomicron. Anaerobe. 2020;64:102232. [DOI] [PubMed]

47.

Lu J, Francis JD, Guevara MA, Moore RE, Chambers SA, Doster RS, et al. Antibacterial and Anti-biofilm Activity of the Human Breast Milk Glycoprotein Lactoferrin against Group B Streptococcus. Chembiochem. 2021;22:2124–33. [DOI] [PubMed] [PMC]

48.

Lu J, Guevara MA, Francis JD, Spicer SK, Moore RE, Chambers SA, et al. Analysis of Susceptibility to the Antimicrobial and Anti-Biofilm Activity of Human Milk Lactoferrin in Clinical Strains of Streptococcus agalactiae With Diverse Capsular and Sequence Types. Front Cell Infect Microbiol. 2021;11:740872. [DOI] [PubMed] [PMC]

49.

Godoy-Gallardo M, Mas-Moruno C, Fernández-Calderón MC, Pérez-Giraldo C, Manero JM, Albericio F, et al. Covalent immobilization of hLf1-11 peptide on a titanium surface reduces bacterial adhesion and biofilm formation. Acta Biomater. 2014;10:3522–34. [DOI] [PubMed]

50.

Kamiya H, Ehara T, Matsumoto T. Inhibitory effects of lactoferrin on biofilm formation in clinical isolates of Pseudomonas aeruginosa. J Infect Chemother. 2012;18:47–52. [DOI] [PubMed]

51.

Xu G, Xiong W, Hu Q, Zuo P, Shao B, Lan F, et al. Lactoferrin-derived peptides and Lactoferricin chimera inhibit virulence factor production and biofilm formation in Pseudomonas aeruginosa. J Appl Microbiol. 2010;109:1311–8. [DOI] [PubMed]

52.

Wakabayashi H, Yamauchi K, Kobayashi T, Yaeshima T, Iwatsuki K, Yoshie H. Inhibitory effects of lactoferrin on growth and biofilm formation of Porphyromonas gingivalis and Prevotella intermedia. Antimicrob Agents Chemother. 2009;53:3308–16. [DOI] [PubMed] [PMC]

53.

Avery TM, Boone RL, Lu J, Spicer SK, Guevara MA, Moore RE, et al. Analysis of Antimicrobial and Antibiofilm Activity of Human Milk Lactoferrin Compared to Bovine Lactoferrin against Multidrug Resistant and Susceptible Acinetobacter baumannii Clinical Isolates. ACS Infect Dis. 2021;7:2116–26. [DOI] [PubMed] [PMC]

54.

Coveñas C, Dextre G, Fernandez D, Mosquito S, Ochoa T. Effect of bovine lactoferrin biofilms in the formation of clinical strains of enteroaggregative E. coli. Rev Peru Med Exp Salud Publica. 2014;31:454–60. Spanish. [PubMed]

55.

Angulo-Zamudio UA, Vidal JE, Nazmi K, Bolscher JGM, Leon-Sicairos C, Antezana BS, et al. Lactoferrin Disaggregates Pneumococcal Biofilms and Inhibits Acquisition of Resistance Through Its DNase Activity. Front Microbiol. 2019;10:2386. [DOI] [PubMed] [PMC]

56.

Lu J, Haley KP, Francis JD, Guevara MA, Doster RS, Craft KM, et al. The Innate Immune Glycoprotein Lactoferrin Represses the Helicobacter pylori cag Type IV Secretion System. Chembiochem. 2021;22:2783–90. [DOI] [PubMed] [PMC]

57.

Ramírez-Rico G, Martinez-Castillo M, Ruiz-Mazón L, Meneses-Romero EP, Palacios JAF, Díaz-Aparicio E, et al. Identification, Biochemical Characterization, and In Vivo Detection of a Zn-Metalloprotease with Collagenase Activity from Mannheimia haemolytica A₂. Int J Mol Sci. 2024;25:1289. [DOI] [PubMed] [PMC]

58.

Ke C, Lan Z, Hua L, Ying Z, Humina X, Jia S, et al. Iron metabolism in infants: influence of bovine lactoferrin from iron-fortified formula. Nutrition. 2015;31:304–9. [DOI] [PubMed]

59.

Chen K, Chai L, Li H, Zhang Y, Xie H, Shang J, et al. Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial. Nutrition. 2016;32:222–7. [DOI] [PubMed]

60.

Okuda M, Nakazawa T, Yamauchi K, Miyashiro E, Koizumi R, Booka M, et al. Bovine lactoferrin is effective to suppress Helicobacter pylori colonization in the human stomach: a randomized, double-blind, placebo-controlled study. J Infect Chemother. 2005;11:265–9. [DOI] [PubMed]

61.

Ajello M, Greco R, Giansanti F, Massucci MT, Antonini G, Valenti P. Anti-invasive activity of bovine lactoferrin towards group A streptococci. Biochem Cell Biol. 2002;80:119–24. [DOI] [PubMed]

62.

Superti F. Lactoferrin from Bovine Milk: A Protective Companion for Life. Nutrients. 2020;12:2562. [DOI] [PubMed] [PMC]