Insights into the mode of action of the two-peptide lantibiotic haloduracin.
Haloduracin, a recently discovered two-peptide lantibiotic composed of the post-translationally modified peptides Halalpha and Halbeta, is shown to have high potency against a range of Gram-positive bacteria and to inhibit spore outgrowth of Bacillus anthracis. The two peptides display optimal activity in a 1:1 stoichiometry and have efficacy similar to that of the commercially used lantibiotic nisin. However, haloduracin is more stable at pH 7 than nisin. Despite significant structural differences between the two peptides of haloduracin and those of the two-peptide lantibiotic lacticin 3147, these two systems show similarities in their mode of action. Like Ltnalpha, Halalpha binds to a target on the surface of Gram-positive bacteria, and like Ltnbeta, the addition of Halbeta results in pore formation and potassium efflux. Using Halalpha mutants, its B- and C-thioether rings are shown to be important but not required for bioactivity. A similar observation was made with mutants of Glu22, a residue that is highly conserved among several lipid II-binding lantibiotics such as mersacidin.
Oman
Trent J
TJ
Department of Chemistry, University of Illinois at Urbana-Champaign and the Howard Hughes Medical Institute, Urbana, Illinois 61801, USA.
van der Donk
Wilfred A
WA
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001407:Bacillus / Q000378:metabolism*; D001430:Bacteriocins / Q000235:genetics / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009561:Nisin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; C515824:haloduracin, Bacillus halodurans; D009561:Nisin
J Biol Chem. 1999 Dec 31;274(53):37544-50
10608807
Annu Rev Microbiol. 2007;61:477-501
17506681
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17243-8
17085596
Microbiology (Reading). 2000 Sep;146 ( Pt 9):2147-2154
10974102
Appl Environ Microbiol. 2003 Jul;69(7):3777-83
12839744
J Bacteriol. 1984 Oct;160(1):442-4
6434524
Antimicrob Agents Chemother. 1998 Jan;42(1):154-60
9449277
Chem Biol. 2008 Oct 20;15(10):1035-45
18940665
Appl Environ Microbiol. 1995 Aug;61(8):2873-8
7487019
Mol Microbiol. 1998 Oct;30(2):317-27
9791177
Science. 1999 Dec 17;286(5448):2245, 2247
10636775
Microbiology (Reading). 2001 Mar;147(Pt 3):643-651
11238971
J Antibiot (Tokyo). 1992 Jun;45(6):832-8
1500347
Appl Environ Microbiol. 1998 Dec;64(12):4803-8
9835565
J Antimicrob Chemother. 1998 Aug;42(2):277-8
9738856
Antimicrob Agents Chemother. 2008 Dec;52(12):4281-8
18809941
Chem Rev. 2005 Feb;105(2):633-84
15700960
Antimicrob Agents Chemother. 2005 Jul;49(7):2606-11
15980326
Appl Environ Microbiol. 1998 Jul;64(7):2335-40
9647795
Biochem J. 1992 Apr 15;283 ( Pt 2):413-20
1575686
Biochemistry. 2008 Jul 15;47(28):7342-51
18570437
Science. 1999 Dec 17;286(5448):2361-4
10600751
Appl Environ Microbiol. 1996 Feb;62(2):385-92
8593044
FEMS Microbiol Lett. 2007 Feb;267(1):64-71
17233677
Mol Microbiol. 2006 Jul;61(2):271-3
16771845
Eur J Biochem. 1996 Nov 1;241(3):716-22
8944757
Curr Opin Chem Biol. 2002 Dec;6(6):786-93
12470732
Eur J Biochem. 1995 Mar 15;228(3):786-97
7737178
Appl Environ Microbiol. 1997 Jul;63(7):2654-9
16535641
J Bacteriol. 1959 Jun;77(6):766-70
13664658
Biochemistry. 2004 Mar 23;43(11):3049-56
15023056
Appl Environ Microbiol. 1996 Aug;62(8):2966-9
8702290
Lett Appl Microbiol. 1999 May;28(5):355-8
10347889
J Bacteriol. 1991 Nov;173(22):7387-90
1938928
FEBS Lett. 2005 Mar 28;579(9):1917-22
15792796
Antimicrob Agents Chemother. 2000 Apr;44(4):827-34
10722477
Appl Environ Microbiol. 1995 Nov;61(11):3894-903
8526502
Curr Protein Pept Sci. 2005 Feb;6(1):61-75
15638769
Antonie Van Leeuwenhoek. 1996 Feb;69(2):161-69
8775976
Chem Biol. 2006 Oct;13(10):1109-17
17052615
Eur J Biochem. 2000 Feb;267(3):901-9
10651829
Nat Rev Drug Discov. 2006 Apr;5(4):321-32
16531990
Mol Microbiol. 2006 Jul;61(2):285-96
16771847