Therapeutic compounds targeting Lipid II for antibacterial purposes

Figures & data

Figure 1 Membrane bound processes in the bacterial cell wall biosynthesis cycle. Lipid II binding antibiotics are shown corresponding to the step in the cycle that they inhibit.

Note: *varying per species.²

Abbreviations: G, N-acetyl glucosamine; M, N-acetyl muramic acid; MraY, phospho-MurNAc-pentapeptide translocase; MurG, Undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase; UMP, uridine monophosphate; UDP, uridine diphosphate.

Table 1 Summarizes the four main classes of peptide antibiotics that target Lipid II: 1) glycopeptides, including the novel generation of lipoglycopeptides; 2) cyclic depsipeptide antibiotics; and 3) the lantibiotic group and 4) more recently, defensins

Class	Antibiotic or subclass	Stage of development	Described interaction with Lipid II	Refs
Glycopeptides	Vancomycin	Clinical use	Binds to terminal D-alanyl-D-alanine part of the pentapeptide side chain of MurNAc.	^Citation16
	Teicoplanin	Clinical use (Europe)	Similar to vancomycin (D-Ala-D-Ala domain of pentapeptide)	^Citation17
	Telavancin	Clinical use	Similar to vancomycin (D-Ala-D-Ala domain of pentapeptide)	^Citation18
	Dalbavancin	Clinical use	Similar to vancomycin (D-Ala-D-Ala domain of pentapeptide)	^Citation19
	Oritavancin	Clinical use	D-Ala-D-Ala domain of pentapeptide and additional motif at the lipid II stem peptide (crossbridge and the D-iso-glutamine in position 2)	^Citation20,Citation21
	Mannopeptimycin	Preclinical	Unknown	^Citation22
Cyclic depsipeptide antibiotics	Katanosin B (lysobactin)	Preclinical	Complex formation with Lipid I, II and Lipid IIA (1:1)	^Citation23
	Plusbacin A3	Preclinical	Inhibition of PG chain extension by transglycosylation	^Citation24
	Ramoplanin	Phase III	Probably hydrogen bonds from the backbone NH groups of ramoplanin bind to the pyrophosphate moiety of Lipid II (2:1).	^Citation25
	Bacitracin		C55-PP	^Citation26
	Friulimicin		C55-PP	^Citation27
	Teixobactin	Preclinical	Probably hydrogen-bond interact-ions with the pyrophosphate moiety of Lipid II	^Citation28
Lantibiotics	Nisin	Preclinical	N-terminus lantinionine ring binds to pyrophosphate moiety via direct hydrogen bonding with polypeptide backbone of nisin. Also minor interactions with the first isoprene unit and the MurNAc sugar have been assumed.	^Citation29
Type A I	Subtilin	Preclinical	Similar to nisin (no structural differences in key positions)	^Citation30
(linear peptide)	Epidermin	Preclinical	Similar to nisin (no structural differences in key positions)	^Citation31
	Mutacin 1140	Preclinical	Similar to nisin (no structural differences in key positions)	^Citation32
Lantibiotics	Nukacin ISK-1	Preclinical	Based on structural similarity to mersacidin and positional significance of the amino acids in the region of ring A lipid II binding similar to mersacacidin is assumed	^Citation33
Type A II(both linear and globular)
	Lacticin 481	Preclinical	Unknown	^Citation34
Lantibiotics	Mersacidin	Preclinical	Complexing the sugar phosphate group, electrostatic interactions and conformational changes are supposed to contribute to this interaction.	^Citation35
Type B(globular peptide)	Plantaricin C	Preclinical	Binding may be assigned to the same binding motif found in mersacidin but the molecular interaction differs from that between lipid II and mersacidin. An additional linking site might have been found as it contains a highly positively charged N terminus, which is missing in mersacidin.	^Citation36
	Pediocin PD-1	Preclinical	Unknown	^Citation37
	Actagardine/gardimycin	Preclinical	Unknown	^Citation38
Two-component lantibiotics (synergistically acting type A I and B structures)	Lacticin 3147	Preclinical	A mersacidin like interaction between the A1 part of lacticin 3147 en lipid II is proposed.	^Citation39
Nonlantibiotic bacteriocins	Colicin M	Preclinical	Enzymatic cleavage of lipid II between the undecaprenyl and	^Citation40
			1-pyrophospho-MurNAc moiety
	Lactococcin 972	Preclinical	Unknown	^Citation41
Defensins and defensin- based compounds	Plectasin NZ2114	Preclinical	The pyrophosphate moiety forms hydrogen bonds to F2, G3 and C37 on plectasin. The D-gamma-glutamate of Lipid II forms a salt bridge with the N-terminus of plectasin and the side-chain of His18.	^Citation15
	Oryzeacin	Preclinical	Unknown
	Eurocin	Preclinical	Unknown
	Lucifensin	Preclinical	Unknown
	Gallicin	Preclinical	Unknown
	HNP-1	Preclinical	Interactions with MurNac, phosphate cage and isoprenyl units	^Citation13
	BAS0012758	Preclinical	Interactions with MurNac, phosphate cage and isoprenyl units	^Citation42
	6Jc48-1	Preclinical	Interactions with MurNac, phosphate cage and isoprenyl units	^Citation43

Note: Data from references.^13–15

van Heijenoort J. Lipid intermediates in the biosynthesis of bacterial peptidoglycan. Microbiol Mol Biol Rev. 2007;71(4):620–635. doi:10.1128/MMBR.00016-0718063720

 PubMed Web of Science ®Google Scholar

Knox JR, Pratt RF. Different modes of vancomycin and D-alanyl-D-alanine peptidase binding to cell wall peptide and a possible role for the vancomycin resistance protein. Antimicrob Agents Chemother. 1990;34(7):1342–1347. doi:10.1128/aac.34.7.13422386365

 PubMed Web of Science ®Google Scholar

Somma S, Gastaldo L, Corti A. Teicoplanin, a new antibiotic from Actinoplanes teichomyceticus nov. sp. Antimicrob Agents Chemother. 1984;26(6):917–923. doi:10.1128/aac.26.6.9176240963

 PubMed Web of Science ®Google Scholar

King A, Phillips I, Kaniga K. Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria. J Antimicrob Chemother. 2004;53(5):797–803. doi:10.1093/jac/dkh15615028667

 PubMed Web of Science ®Google Scholar

Woodford N. Novel agents for the treatment of resistant Gram-positive infections. Expert Opin Investig Drugs. 2003;12(2):117–137. doi:10.1517/13543784.12.2.117

 PubMed Web of Science ®Google Scholar

Schwalbe RS, McIntosh AC, Qaiyumi S, et al. In vitro activity of LY333328, an investigational glycopeptide antibiotic, against enterococci and staphylococci. Antimicrob Agents Chemother. 1996;40(10):2416–2419.8891155

 PubMed Web of Science ®Google Scholar

Munch D, Engels I, Muller A, et al. Structural variations of the cell wall precursor lipid II and their influence on binding and activity of the lipoglycopeptide antibiotic oritavancin. Antimicrob Agents Chemother. 2015;59(2):772–781. doi:10.1128/AAC.02663-1425403671

 PubMed Web of Science ®Google Scholar

Singh MP, Petersen PJ, Weiss WJ, et al. Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: antibacterial and mechanistic activities. Antimicrob Agents Chemother. 2003;47(1):62–69. doi:10.1128/aac.47.1.62-69.200312499170

 PubMed Web of Science ®Google Scholar

Lee W, Schaefer K, Qiao Y, et al. The Mechanism of Action of Lysobactin. J Am Chem Soc. 2016;138(1):100–103. doi:10.1021/jacs.5b1180726683668

 PubMed Web of Science ®Google Scholar

O’Connor RD, Singh M, Chang J, et al. Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus. J Phys Chem B. 2017;121(7):1499–1505. doi:10.1021/acs.jpcb.6b1103928135800

 PubMed Web of Science ®Google Scholar

Reynolds PE, Somner EA. Comparison of the target sites and mechanisms of action of glycopeptide and lipoglycodepsipeptide antibiotics. Drugs Exp Clin Res. 1990;16(8):385–389.2151441

 PubMedGoogle Scholar

Stone KJ, Strominger JL. Mechanism of action of bacitracin: complexation with metal ion and C 55 -isoprenyl pyrophosphate. Proc Natl Acad Sci U S A. 1971;68(12):3223–3227. doi:10.1073/pnas.68.12.32234332017

 PubMed Web of Science ®Google Scholar

Vertesy L, Ehlers E, Kogler H, et al. Friulimicins: novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friuliensis sp. nov. II. Isolation and structural characterization. J Antibiot (Tokyo). 2000;53(8):816–827. doi:10.7164/antibiotics.53.81611079804

 PubMed Web of Science ®Google Scholar

Zong Y, Sun X, Gao H, et al. Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin. J Med Chem. 2018;61(8):3409–3421. doi:10.1021/acs.jmedchem.7b0124129629769

 PubMed Web of Science ®Google Scholar

Breukink E, Wiedemann I, van Kraaij C, et al. Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic. Science. 1999;286(5448):2361–2364. doi:10.1126/science.286.5448.236110600751

 PubMed Web of Science ®Google Scholar

Nakano MM, Zuber P. Molecular biology of antibiotic production in Bacillus. Crit Rev Biotechnol. 1990;10(3):223–240. doi:10.3109/073885590090382091702690

 PubMed Web of Science ®Google Scholar

Schnell N, Entian KD, Schneider U, et al. Prepeptide sequence of epidermin, a ribosomally synthesized antibiotic with four sulphide-rings. Nature. 1988;333(6170):276–278. doi:10.1038/333276a02835685

 PubMed Web of Science ®Google Scholar

Smith L, Hasper H, Breukink E, et al. Elucidation of the antimicrobial mechanism of mutacin 1140. Biochemistry. 2008;47(10):3308–3314. doi:10.1021/bi701262z18266322

 PubMed Web of Science ®Google Scholar

Sashihara T, Kimura H, Higuchi T, et al. A novel lantibiotic, nukacin ISK-1, of Staphylococcus warneri ISK-1: cloning of the structural gene and identification of the structure. Biosci Biotechnol Biochem. 2000;64(11):2420–2428. doi:10.1271/bbb.64.242011193411

 PubMed Web of Science ®Google Scholar

Demel RA, Peelen T, Siezen RJ, De Kruijff B, Kuipers OP, Nisin Z. mutant nisin Z and lacticin 481 interactions with anionic lipids correlate with antimicrobial activity A monolayer study. Eur J Biochem. 1996;235(1–2):267–274. doi:10.1111/j.1432-1033.1996.00267.x8631341

 PubMedGoogle Scholar

Brötz H, Bierbaum G, Markus A, Molitor E, Sahl HG. Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism? Antimicrob Agents Chemother. 1995;39(3):714–719. doi:10.1128/aac.39.3.7147793878

 PubMed Web of Science ®Google Scholar

Bauer R, Dicks LM. Mode of action of lipid II-targeting lantibiotics. Int J Food Microbiol. 2005;101(2):201–216. doi:10.1016/j.ijfoodmicro.2004.11.00715862882

 PubMed Web of Science ®Google Scholar

Montville TJ, Chen Y. Mechanistic action of pediocin and nisin: recent progress and unresolved questions. Appl Microbiol Biotechnol. 1998;50(5):511–519.9917136

 PubMed Web of Science ®Google Scholar

Somma S, Merati W, Parenti F. Gardimycin, a new antibiotic inhibiting peptidoglycan synthesis. Antimicrob Agents Chemother. 1977;11(3):396–401. doi:10.1128/aac.11.3.396404960

 PubMed Web of Science ®Google Scholar

Wiedemann I, Bottiger T, Bonelli RR, et al. The mode of action of the lantibiotic lacticin 3147–a complex mechanism involving specific interaction of two peptides and the cell wall precursor lipid II. Mol Microbiol. 2006;61(2):285–296. doi:10.1111/j.1365-2958.2006.05223.x16771847

 PubMed Web of Science ®Google Scholar

El Ghachi M, Bouhss A, Barreteau H, et al. Colicin M exerts its bacteriolytic effect via enzymatic degradation of undecaprenyl phosphate-linked peptidoglycan precursors. J Biol Chem. 2006;281(32):22761–22772. doi:10.1074/jbc.M60283420016777846

 PubMed Web of Science ®Google Scholar

Martinez B, Suarez JE, Rodriguez A. Lactococcin 972: a homodimeric lactococcal bacteriocin whose primary target is not the plasma membrane. Microbiology. 1996;142(Pt 9):2393–2398. doi:10.1099/00221287-142-9-239321818877

 PubMed Web of Science ®Google Scholar

Schneider T, Kruse T, Wimmer R, et al. Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II. Science. 2010;328(5982):1168–1172. doi:10.1126/science.118572320508130

 PubMed Web of Science ®Google Scholar

de Leeuw E, Li C, Zeng P, et al. Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett. 2010;584(8):1543–1548. doi:10.1016/j.febslet.2010.03.00420214904

 PubMed Web of Science ®Google Scholar

Varney KM, Bonvin AM, Pazgier M, et al. Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. PLoS Pathog. 2013;9(11):e1003732. doi:10.1371/journal.ppat.100373224244161

 PubMed Web of Science ®Google Scholar

Chauhan J, Cardinale S, Fang L, et al. Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics. PLoS One. 2016;11(10):e0164515. doi:10.1371/journal.pone.016451527776124

 PubMed Web of Science ®Google Scholar