title: Combination of alpha-melanocyte stimulating hormone with conventional antibiotics against methicillin resistant Staphylococcus aureus.
abstract: Our previous studies revealed that alpha-melanocyte stimulating hormone (α-MSH) is strongly active against Staphylococcus aureus (S. aureus) including methicillin resistant S. aureus (MRSA). Killing due to α-MSH occurred by perturbation of the bacterial membrane. In the present study, we investigated the in vitro synergistic potential of α-MSH with five selected conventional antibiotics viz., oxacillin (OX), ciprofloxacin (CF), tetracycline (TC), gentamicin (GM) and rifampicin (RF) against a clinical MRSA strain which carried a type III staphylococcal cassette chromosome mec (SCCmec) element and belonged to the sequence type (ST) 239. The strain was found to be highly resistant to OX (minimum inhibitory concentration (MIC) = 1024 µg/ml) as well as to other selected antimicrobial agents including α-MSH. The possibility of the existence of intracellular target sites of α-MSH was evaluated by examining the DNA, RNA and protein synthesis pathways. We observed a synergistic potential of α-MSH with GM, CF and TC. Remarkably, the supplementation of α-MSH with GM, CF and TC resulted in ≥ 64-, 8- and 4-fold reductions in their minimum bactericidal concentrations (MBCs), respectively. Apart from membrane perturbation, in this study we found that α-MSH inhibited ≈ 53% and ≈ 47% DNA and protein synthesis, respectively, but not RNA synthesis. Thus, the mechanistic analogy between α-MSH and CF or GM or TC appears to be the reason for the observed synergy between them. In contrast, α-MSH did not act synergistically with RF which may be due to its inability to inhibit RNA synthesis (<10%). Nevertheless, the combination of α-MSH with RF and OX showed an enhanced killing by ≈ 45% and ≈ 70%, respectively, perhaps due to the membrane disrupting properties of α-MSH. The synergistic activity of α-MSH with antibiotics is encouraging, and promises to restore the lost potency of discarded antibiotics.
authors.affiliation: School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Singh
authors.forename: Ravisekhar
authors.initials: R
authors.lastname: Gadepalli
authors.forename: Benu
authors.initials: B
authors.lastname: Dhawan
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mukhopadhyay
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005839:Gentamicins / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability / Q000187:drug effects* / Q000235:genetics; D010068:Oxacillin / Q000494:pharmacology; D012329:RNA, Bacterial / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D005839:Gentamicins; D012329:RNA, Bacterial; D000521:alpha-MSH; D002939:Ciprofloxacin; D013752:Tetracycline; D010068:Oxacillin; D012293:Rifampin
references.citation: Eur J Clin Microbiol Infect Dis. 2013 Jan;32(1):33-42
references.pmid: 22898726
references.citation: Chemother Res Pract. 2011;2011:619321
references.pmid: 22312555
references.citation: Antimicrob Agents Chemother. 2011 Sep;55(9):3977-84
references.pmid: 21730114
references.citation: Antimicrob Agents Chemother. 1983 Apr;23(4):571-6
references.pmid: 6859835
references.citation: Antimicrob Agents Chemother. 1976 Dec;10(6):878-84
references.pmid: 795373
references.citation: Antimicrob Agents Chemother. 2012 Feb;56(2):838-44
references.pmid: 22123698
references.citation: ScientificWorldJournal. 2006 Oct 02;6:1241-6
references.pmid: 17028769
references.citation: Antimicrob Agents Chemother. 2010 Feb;54(2):742-8
references.pmid: 19933808
references.citation: Antimicrob Agents Chemother. 2011 May;55(5):1920-9
references.pmid: 21282427
references.citation: Am J Med. 2006 Jun;119(6 Suppl 1):S3-10; discussion S62-70
references.pmid: 16735149
references.citation: J Dermatol Sci. 2005 Nov;40(2):123-32
references.pmid: 15963694
references.citation: Biotechnol Lett. 2009 Aug;31(8):1265-7
references.pmid: 19396584
references.citation: J Med Chem. 1996 Aug 2;39(16):3107-13
references.pmid: 8759631
references.citation: APMIS. 2010 Nov;118(11):830-6
references.pmid: 20955455
references.citation: Lancet. 2004 Jan 10;363(9403):139-49
references.pmid: 14726169
references.citation: Kidney Int. 2011 Jan;79(1):33-45
references.pmid: 20861826
references.citation: Microbiol Mol Biol Rev. 1997 Sep;61(3):377-92
references.pmid: 9293187
references.citation: Diagn Microbiol Infect Dis. 2011 Aug;70(4):561-4
references.pmid: 21767715
references.citation: Chemotherapy. 2011;57(5):363-71
references.pmid: 21996946
references.citation: Antimicrob Agents Chemother. 1998 Sep;42(9):2206-14
references.pmid: 9736536
references.citation: Clin Infect Dis. 2008 Jun 1;46 Suppl 5:S344-9
references.pmid: 18462089
references.citation: J Clin Microbiol. 2000 Mar;38(3):1008-15
references.pmid: 10698988
references.citation: Antimicrob Agents Chemother. 1978 May;13(5):759-61
references.pmid: 666300
references.citation: FEMS Microbiol Lett. 2009 Mar;292(1):141-8
references.pmid: 19187210
references.citation: Peptides. 2009 Sep;30(9):1627-35
references.pmid: 19560499
references.citation: Peptides. 2010 Oct;31(10):1811-20
references.pmid: 20600422
references.citation: Infect Drug Resist. 2008;1:57-61
references.pmid: 21694881
references.citation: Annu Rev Pharmacol Toxicol. 2012;52:337-60
references.pmid: 22235859
references.citation: J Antimicrob Chemother. 1998 Jun;41(6):605-14
references.pmid: 9687098
references.citation: J Pept Sci. 2010 Jul;16(7):337-41
references.pmid: 20552564
references.citation: Cell. 2001 Mar 23;104(6):901-12
references.pmid: 11290327
references.citation: Clin Microbiol Rev. 2007 Jul;20(3):391-408, table of contents
references.pmid: 17630331
references.citation: Antimicrob Agents Chemother. 2011 Jan;55(1):311-20
references.pmid: 20937782
references.citation: Antimicrob Agents Chemother. 2007 Apr;51(4):1504-7
references.pmid: 17220402
references.citation: Peptides. 2012 Oct;37(2):334-9
references.pmid: 22835936
references.citation: Antimicrob Agents Chemother. 1999 May;43(5):1111-7
references.pmid: 10223922
references.citation: Clin Microbiol Infect. 2008 Jul;14(7):670-6
references.pmid: 18558939
references.citation: Annu Rev Pharmacol. 1968;8:151-70
references.pmid: 4875390
references.citation: Antimicrob Agents Chemother. 2009 Jun;53(6):2636-7
references.pmid: 19289517
references.citation: Antimicrob Agents Chemother. 2002 Jul;46(7):2155-61
references.pmid: 12069968
references.citation: Nat Rev Microbiol. 2009 Sep;7(9):629-41
references.pmid: 19680247
references.citation: PLoS One. 2010 Jan 05;5(1):e8582
references.pmid: 20062529
references.citation: Curr Drug Targets Infect Disord. 2002 Mar;2(1):79-83
references.pmid: 12462155
references.citation: Antimicrob Agents Chemother. 2011 Sep;55(9):4176-82
references.pmid: 21690282
references.citation: J Antimicrob Chemother. 2006 Mar;57(3):498-505
references.pmid: 16410264
references.citation: J Antimicrob Chemother. 2006 Jul;58(1):108-11
references.pmid: 16735429
references.citation: Antimicrob Agents Chemother. 1974 Oct;6(4):411-4
references.pmid: 4157335
references.citation: JAMA. 2007 Oct 17;298(15):1763-71
references.pmid: 17940231
references.citation: Biochim Biophys Acta. 2006 Jan;1764(1):24-32
references.pmid: 16344012
references.citation: J Hosp Infect. 2009 Nov;73(3):253-63
references.pmid: 19782432
references.citation: J Infect Dis. 2008 Apr 15;197(8):1079-81
references.pmid: 18419525
references.citation: Surg Infect (Larchmt). 2011 Jun;12(3):191-203
references.pmid: 21812657
references.citation: Nature. 2002 Jan 24;415(6870):389-95
references.pmid: 11807545
references.citation: Pharmacogn Mag. 2012 Jan;8(29):60-4
references.pmid: 22438665
references.citation: Endocrinology. 2004 Jul;145(7):3165-73
references.pmid: 15033915