Drug limitation of the availability of iron ions for pathogenic bacteria (part 2)

А.Е. Abaturov, Т.А. Kryuchko


Existing effective methods of treatment designed to control the level of iron supply to the bacteria are based on the use of drugs that chelate iron ions, inhibit the mechanisms of siderophore synthesis; replace trivalent iron with trivalent gallium delivering antimicrobial agents or gallium into the bacterium. However, the current state of the issue has not run out the potential of existing methods of therapy, and yet not all possible mechanisms to control the exchange of iron in bacteria are being used. In particular, the strain-specific mechanisms of absorption inhibition in iron-loaded siderophores and methods to isolate iron ions from bacteria are essentially unexplored. Also, studies on the functioning of the lipocalin system will make it possible to use this evolutionary way for the protection against infectious agents in medical practice. Drug control over the iron supply to the pathogenic bacteria open the potential for future scientific researches in view of the high degree of dependence of the vital activity of microorganisms and the level of bacterial virulence on the accessibility of the iron pool. Undoubtedly, the studies will lead to the development of new therapeutic approaches to the treatment of infectious diseases.


pneumonia; iron; pathogenic bacteria; iron supply management


Arnold C, Chaffin MK, Cohen N, Fajt VR, Taylor RJ, Bernstein LR. Pharmacokinetics of gallium maltolate after intragastric administration in adult horses. Am J Vet Res. 2010 Nov;71(11):1371-6. doi: 10.2460/ajvr.71.11.1371.

Atala A. Re: Cellular Uptake and Anticancer Activity of Carboxylated Gallium Corroles. J Urol. 2016 Nov;196(5):1584-1585. doi: 10.1016/j.juro.2016.08.022.

Ballouche M, Cornelis P, Baysse C. Iron metabolism: a promising target for antibacterial strategies. Recent Pat Antiinfect Drug Discov. 2009 Nov;4(3):190-205.

Banin E, Lozinski A, Brady KM, et al. The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16761-6. doi: 10.1073/pnas.0808608105.

Bernstein LR. Ga Therapeutic Gallium Compounds. In: Gielen M, Tiekink ERT, editors. Metallotherapeutic Drugs and Metal‐Based Diagnostic Agents: The Use of Metals in Medicine, Ch 14. England: John Wiley & Sons, Ltd; 2005. 259-277 pp. doi: 10.1002/0470864052.ch14.

Bonchi C, Frangipani E, Imperi F, Visca P. Pyoverdine and proteases affect the response of Pseudomonas aeruginosa to gallium in human serum. Antimicrob Agents Chemother. 2015 Sep;59(9):5641-6. doi: 10.1128/AAC.01097-15.

Braun V, Pramanik A, Gwinner T, Köberle M, Bohn E. Sideromycins: tools and antibiotics. Biometals. 2009 Feb;22(1):3-13. doi: 10.1007/s10534-008-9199-7.

Chen M, Wang Y, Gilliard RJ Jr, Wei P, Schwartz NA, Robinson GH. Synthesis and molecular structure of an abnormal carbene-gallium chloride complex. Dalton Trans. 2014 Oct 14;43(38):14211-4. doi: 10.1039/c4dt00933a.

Chevalier S, Bouffartigues E, Bodilis J, et al. Structure, function and regulation of Pseudomonas aeruginosa porins. FEMS Microbiol Rev. 2017 Sep 1;41(5):698-722. doi: 10.1093/femsre/fux020.

Chitambar CR. Gallium and its competing roles with iron in biological systems. Biochim Biophys Acta. 2016 Aug;1863(8):2044-53. doi: 10.1016/j.bbamcr.2016.04.027.

Chitambar CR. The therapeutic potential of iron-targeting gallium compounds in human disease: From basic research to clinical application. Pharmacol Res. 2017 Jan;115:56-64. doi: 10.1016/j.phrs.2016.11.009.

Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? Br J Pharmacol. 2011 May;163(1):184-94. doi: 10.1111/j.1476-5381.2011.01250.x.

DeLeon K, Balldin F, Watters C, et al. Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice. Antimicrob Agents Chemother. 2009 Apr;53(4):1331-7. doi: 10.1128/AAC.01330-08.

Despaigne AA, Parrilha GL, Izidoro JB, et al. 2-Acetylpyridine- and 2-benzoylpyridine-derived hydrazones and their gallium(III) complexes are highly cytotoxic to glioma cells. Eur J Med Chem. 2012 Apr;50:163-72. doi: 10.1016/j.ejmech.2012.01.051.

Drake EJ, Duckworth BP, Neres J, Aldrich CC, Gulick AM. Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis. Biochemistry. 2010 Nov 2;49(43):9292-305. doi: 10.1021/bi101226n.

Falagas ME, Skalidis T, Vardakas KZ, Legakis NJ; Hellenic Cefiderocol Study Group. Activity of cefiderocol (S-649266) against carbapenem-resistant Gram-negative bacteria collected from inpatients in Greek hospitals. J Antimicrob Chemother. 2017 Jun 1;72(6):1704-1708. doi: 10.1093/jac/dkx049.

Foley TL, Simeonov A. Targeting iron assimilation to develop new antibacterials. Expert Opin Drug Discov. 2012 Sep;7(9):831-47. doi: 10.1517/17460441.2012.708335.

García-Contreras R, Pérez-Eretza B, Lira-Silva E, et al. Gallium induces the production of virulence factors in Pseudomonas aeruginosa. Pathog Dis. 2014 Feb;70(1):95-8. doi: 10.1111/2049-632X.12105.

Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, explored in a pseudomonas aeruginosa neutropenic murine thigh model. Int J Antimicrob Agents. 2017 Oct 27. pii: S0924-8579(17)30372-2. doi: 10.1016/j.ijantimicag.2017.10.008.

Ghequire MG, De Mot R. Ribosomally encoded antibacterial proteins and peptides from Pseudomonas. FEMS Microbiol Rev. 2014 Jul;38(4):523-68. doi: 10.1111/1574-6976.12079.

Górska A, Sloderbach A, Marszałł MP. Siderophore-drug complexes: potential medicinal applications of the 'Trojan horse' strategy. Trends Pharmacol Sci. 2014 Sep;35(9):442-9. doi: 10.1016/

Gulick AM. Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens. Nat Prod Rep. 2017 Aug 2;34(8):981-1009. doi: 10.1039/c7np00029d.

Hider RC, Kong X. Chemistry and biology of siderophores. Nat Prod Rep. 2010 May;27(5):637-57. doi: 10.1039/b906679a.

Hijazi S, Visca P, Frangipani E. Gallium-Protoporphyrin IX Inhibits Pseudomonas aeruginosa Growth by Targeting Cytochromes Front Cell Infect Microbiol. 2017 Jan 26;7:12. doi: 10.3389/fcimb.2017.00012.

Huayhuaz JA, Vitorino HA, Campos OS, Serrano SHP1, Kaneko TM2, Espósito BP. Desferrioxamine and desferrioxamine-caffeine as carriers of aluminum and gallium to microbes via the Trojan Horse Effect. J Trace Elem Med Biol. 2017 May;41:16-22. doi: 10.1016/j.jtemb.2017.01.006.

Ji C, Juárez-Hernández RE, Miller MJ. Exploiting bacterial iron acquisition: siderophore conjugates. Future Med Chem. 2012 Mar;4(3):297-313. doi: 10.4155/fmc.11.191.

Johnstone TC, Nolan EM. Beyond iron: non-classical biological functions of bacterial siderophores. Dalton Trans. 2015 Apr 14;44(14):6320-39. doi: 10.1039/c4dt03559c.

Kaneko Y, Thoendel M, Olakanmi O, Britigan BE, Singh PK. The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Invest. 2007 Apr;117(4):877-88. doi: 10.1172/JCI30783.

Kelson AB, Carnevali M, Truong-Le V. Gallium-based anti-infectives: targeting microbial iron-uptake mechanisms. Curr Opin Pharmacol. 2013 Oct;13(5):707-16. doi: 10.1016/j.coph.2013.07.001.

Kubista B, Schoefl T, Mayr L, et al. Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition. J Exp Clin Cancer Res. 2017 Apr 12;36(1):52. doi: 10.1186/s13046-017-0527-z.

Kumar K. A novel approach of 67-Gallium-citrate three-phase bone scan to diagnose bone infection: A report of three cases. Indian J Nucl Med. 2016 Oct-Dec;31(4):260-266. doi: 10.4103/0972-3919.190801.

Kurth C, Kage H, Nett M. Siderophores as molecular tools in medical and environmental applications. Org Biomol Chem. 2016 Sep 21;14(35):8212-27. doi: 10.1039/c6ob01400c.

Machado I, Marino LB, Demoro B, et al. Bioactivity of pyridine-2-thiolato-1-oxide metal complexes: Bi(III), Fe(III) and Ga(III) complexes as potent anti-Mycobacterium tuberculosis prospective agents. Eur J Med Chem. 2014 Nov 24;87:267-73. doi: 10.1016/j.ejmech.2014.09.067.

McPherson CJ, Aschenbrenner LM, Lacey BM, et al. Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophore-conjugated monocarbam. Antimicrob Agents Chemother. 2012 Dec;56(12):6334-42. doi: 10.1128/AAC.01345-12.

Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev. 2007 Sep;71(3):413-51. doi: 10.1128/MMBR.00012-07.

Minandri F, Bonchi C, Frangipani E et al. Promises and failures of gallium as an antibacterial agent. Future Microbiol. 2014;9(3):379-97. doi: 10.2217/fmb.14.3.

Moynié L, Luscher A, Rolo D, et al. Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii. Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: e02531-16. doi: 10.1128/AAC.02531-16.

Page MG. Siderophore conjugates. Ann N Y Acad Sci. 2013 Jan;1277:115-26. doi: 10.1111/nyas.12024.

Qi J, Zheng Y, Qian K, et al. Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells. J Inorg Biochem. 2017 Dec;177:110-117. doi: 10.1016/j.jinorgbio.2017.09.012.

Rangel-Vega A, Bernstein LR, Mandujano-Tinoco EA, García-Contreras SJ, García-Contreras R. Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections. Front Microbiol. 2015 Apr 9;6:282. doi: 10.3389/fmicb.2015.00282.

Reagan P, Pani A, Rosner MH. Approach to diagnosis and treatment of hypercalcemia in a patient with malignancy. Am J Kidney Dis. 2014 Jan;63(1):141-7. doi: 10.1053/j.ajkd.2013.06.025.

Rhomberg PR, Shortridge D, Huband MD, et al. Multilaboratory broth microdilution MIC reproducibility study for GSK3342830, a novel catecholcephem. In: American Society for Microbiology (ASM Microbe), 1–5 June 2017, New Orleans, Louisiana, USA. North Liberty (IA): JMI Laboratories; 2017.

Richter K, Thomas N, Zhang G, et al. Deferiprone and Gallium-Protoporphyrin Have the Capacity to Potentiate the Activity of Antibiotics in Staphylococcus aureus Small Colony Variants. Front Cell Infect Microbiol. 2017 Jun 22;7:280. doi: 10.3389/fcimb.2017.00280.

Tan L, Tao Y, Wang T, et al. Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections. J Med Chem. 2017 Apr 13;60(7):2669-2684. doi: 10.1021/acs.jmedchem.6b01261.

Thompson MG, Truong-Le V, Alamneh YA, et al. Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of Infection. Antimicrob Agents Chemother. 2015 Oct;59(10):6484-93. doi: 10.1128/AAC.00882-15.

Tripathi A, Schofield MM, Chlipala GE, et al. Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis. J Am Chem Soc. 2014 Jan 29;136(4):1579-86. doi: 10.1021/ja4115924.

Valappil SP, Ready D, Abou Neel EA, et al. Controlled delivery of antimicrobial gallium ions from phosphate-based glasses. Acta Biomater. 2009 May;5(4):1198-210. doi: 10.1016/j.actbio.2008.09.019.

Valappil SP, Yiu HH, Bouffier L, et al. Effect of novel antibacterial gallium-carboxymethyl cellulose on Pseudomonas aeruginosa. Dalton Trans. 2013 Feb 7;42(5):1778-86. doi: 10.1039/c2dt32235h.

Vila-Farres X, Chu J, Inoyama D, et al. Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters. J Am Chem Soc. 2017 Feb 1;139(4):1404-1407. doi: 10.1021/jacs.6b11861.

Wang W, Qiu Z, Tan H, Cao L. Siderophore production by actinobacteria. Biometals. 2014 Aug;27(4):623-31. doi: 10.1007/s10534-014-9739-2.

Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017 Oct;23(10):704-712. doi: 10.1016/j.cmi.2017.09.001.

Zanias S, Papaefstathiou GS, Raptopoulou CP, et al. Synthesis, Structure, and Antiproliferative Activity of Three Gallium(III) Azole Complexes. Bioinorg Chem Appl. 2010;2010. pii: 168030. doi: 10.1155/2010/168030.

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