Abstract
Seven conjugates composed of well-known fluoroquinolone antibacterial agents, ciprofloxacin (CIP) or levofloxacin (LVX), and a cell-penetrating peptide transportan 10 (TP10-NH2) were synthesised. The drugs were covalently bound to the peptide via an amide bond, methylenecarbonyl moiety, or a disulfide bridge. Conjugation of fluoroquinolones to TP10-NH2 resulted in congeners demonstrating antifungal in vitro activity against human pathogenic yeasts of the Candida genus (MICs in the 6.25–100 µM range), whereas the components were poorly active. The antibacterial in vitro activity of most of the conjugates was lower than the activity of CIP or LVX, but the antibacterial effect of CIP-S-S-TP10-NH2 was similar to the mother fluoroquinolone. Additionally, for two representative CIP and LVX conjugates, a rapid bactericidal effect was shown. Compared to fluoroquinolones, TP10-NH2 and the majority of its conjugates generated a relatively low level of reactive oxygen species (ROS) in human embryonic kidney cells (HEK293) and human myeloid leukemia cells (HL-60). The conjugates exhibited cytotoxicity against three cell lines, HEK293, HepG2 (human liver cancer cell line), and LLC-PK1 (old male pig kidney cells), with IC50 values in the 10–100 µM range and hemolytic activity. The mammalian toxicity was due to the intrinsic cytoplasmic membrane disruption activity of TP10-NH2 since fluoroquinolones themselves were not cytotoxic. Nevertheless, the selectivity index values of the conjugates, both for the bacteria and human pathogenic yeasts, remained favourable.
Highlights
Levofloxacin (LVX) and ciprofloxacin (CIP) are broad-spectrum fluoroquinolone synthetic chemotherapeutics, active against both Gram-positive and Gram-negative bacteria
One of the possibilities to alter the biological properties of chemotherapeutic agents is their chemical modification, including conjugation with oligopeptides, especially those known as the cell-penetrating peptides (CPPs)
In our recent paper [10], we showed that ciprofloxacin conjugated through a disulfide bridge with the antimicrobial peptide named HLopt2 entered microbial cells
Summary
Levofloxacin (LVX) and ciprofloxacin (CIP) are broad-spectrum fluoroquinolone synthetic chemotherapeutics, active against both Gram-positive and Gram-negative bacteria. One of the possibilities to alter the biological properties of chemotherapeutic agents is their chemical modification, including conjugation with oligopeptides, especially those known as the cell-penetrating peptides (CPPs). Such conjugates may possess additional advantages, including an increased selectivity of drug delivery, enhanced efficacy, reduced systemic toxicity, as well as improved pharmacokinetics and pharmacodynamics. A shorter variant of TP, with deletion of the N-terminal hexapeptide, named TP10-NH2, having an amide moiety at the C-terminus, retains the efficient cell penetration property of the parent compound, with significantly less potential side effects [18] This peptide amide enters all cell types, including the mammalian ones, and inhibits the growth of some microorganisms, such as Candida albicans, Staphylococcus aureus [19], Streptococcus pneumoniae, and Mycobacterium tuberculosis [20]. IIPn-TCPIP10-T-NP1H02-N(2H), 2an(2a)m, aindeabmoindde wboansdfowrmasedfobremtwedeebnetthweeceanrbthoexyclagrbroouxpylogfrCoIuPpaonfdCIP the apnedpttihdee pαe-pamtidineoαg-aromuipn.oAgnroiunpte.rAmnolienctuelramr odliescuulflaidredbisruidlfigde,esbpraindngien,gspbaonthnicnogmbpoothnecnotms pinonCeInPt-s in S-S-CTIPP1-0S--NS-HTP2 1(30)-,NwHa2s(f3o)r,mweads fuosrimngedthuesiLnogmthaentL’somreaangte’ns tr,edagitehniot,-bdiist(hsiuoc-bciins(ismuicdcyinl ipmriodpyilopnarotep)i.oInnate). the ILnVtXhe-bLaVseXd-bcaosnejdugcoantejuLgVatXe-TLVP1X0--TNPH102-N(4H), 2th(4e)L, tVhXe LcVarXbocxaryblogxryolugprowuapswlinaskelidnkweidthwtihthe tαh-eamα-ianmo ino grougprooufpToPf1T0P-N10H-N2.HIn2.LIVnXLCV-XSC-S--SC-ST-PC1T0P-N10H-N2 (H5)2a(n5)daCnIdPCCI-PS-CS--SC-TS-PC1T0P-N10H-N2 (H6), (t6h)e, tdhiesudlfisiduelfibdreidbgreidge waswfaosrmfoerdmbeyd CbyysCryessirdeusiedsu, aetst,aacthtaecdhteodbtoothboLthVXLVoXr CorIPCaIPndanthdethNe-tNer-mteirnmuisnoufs ToPf 1T0P-1N0H-N2.HIt2.wIatswas perfpoerrmfoerdmbeyd tbhyetihnetriondtruocdtuiocntioonf tohfethSe-(S3--(n3i-tnroit-r2o--p2y-priydryidlsyulslfualnfaynl)yl()N(Npypsy)sg)rgoruopuptotothtehethtihoiloflufunnctcitoionn of of CCyyssaatttatacchheeddtotoBBoocc-C-CIPIPoorrLLVVXX..IInnoorrddeerrttooddeetteerrmmiinneetthheecceelllluullaarr uuppttaakkee ooff 11,, iittss lflauboerlleesdceanntalylolgabueelled CIPa-CnaHlo2CgOue-TCPI1P0-(CCHf)2-NCOH-2TP(71)0,(CTfP)-1N0(HC2f)(-N7)H, T2,P1a0n(Cdf )C-NIPH(C2,f)an(dreCfeIrPe(nCcfe) (rceofmerpeonucendcos)mpwoeurendasl)swo ere synathlseosissyedn.thInestihseedfi.rsInt ttwheo ficorsmt ptwouoncdosm, 5p(o6u)-ncadrsb,o5x(y6)f-lucaorrbeoscxeyiflnuwoaressactetianchweadstaottthacehεe-damtointohegrεo-aump ino of thgrteouppepoftitdhet’espLeypstidrees’isdLuyes trhesaitdrueeptlhaactedrepAllaaceind Apolasiitniopnos1i2ti,own h12e,rewahseirneaCsIiPn(CCIfP),(Cthfe),ftlhueoflroupohrooprehore waswinastriondtruocdeudcteodthtoetchheecmhoetmhoerthapereauptiecuatimc ianmoignroogurpo.up
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