Abstract
Background: Human infectious diseases caused by bacteria are a worldwide health problem due to the increased resistance of these microorganisms to conventional antibiotics. For this reason, the identification of novel molecular targets and the discovery of new antibacterial compounds are urgently required. Metalo-aminopeptidases are promising targets in bacterial infections. They participate in crucial processes for bacterial growth and pathogenesis, such as protein and peptide degradation to supply amino acids, protein processing, access to host tissues, cysteine supply for redox control, transcriptional regulation, site-specific DNA recombination, and hydrogen sulfide production. Although several of these enzymes are not essential, they are required for virulence and maximal growth in conditions of nutrient limitation and high temperatures.
Objective: In this review, we describe the structural, functional, and kinetic properties of some examples of bacterial metalo-aminopeptidases, in the context of their use as antibacterial targets. In addition, we present some inhibitors reported for these enzymes.
Conclusion: It is necessary to conduct a meticulous work to validate these peptidases as good/bad targets and to identify inhibitors with potential therapeutic use.
Keywords: Antibacterial agents, divalent metallic cations, enzyme-inhibitor complexes, metalo-aminopeptidases, pathogenic bacteria, protease inhibitors.
[http://dx.doi.org/10.1096/fasebj.7.2.8440407] [PMID: 8440407]
[http://dx.doi.org/10.1017/S0022029900026868]
[http://dx.doi.org/10.1128/aem.57.9.2447-2452.1991] [PMID: 1768119]
[http://dx.doi.org/10.1146/annurev.bi.43.070174.004155] [PMID: 4604628]
[http://dx.doi.org/10.1146/annurev.bi.45.070176.003531] [PMID: 786161]
[http://dx.doi.org/10.1016/0168-6445(89)90035-1] [PMID: 2698230]
[http://dx.doi.org/10.1146/annurev.mi.29.100175.002413] [PMID: 1101808]
[http://dx.doi.org/10.1099/00221287-137-5-1207]
[http://dx.doi.org/10.1093/nar/gkt953] [PMID: 24157837]
[http://dx.doi.org/10.1111/j.1567-1364.2008.00411.x] [PMID: 18637841]
[http://dx.doi.org/10.2174/0929866043406643] [PMID: 15544570]
[http://dx.doi.org/10.1074/jbc.M404369200] [PMID: 15263000]
[http://dx.doi.org/10.1111/j.1471-4159.2004.02916.x] [PMID: 15686482]
[http://dx.doi.org/10.1016/S0090-6980(02)00051-5] [PMID: 12432939]
[http://dx.doi.org/10.1016/S0378-1119(02)00650-9] [PMID: 12119107]
[http://dx.doi.org/10.1074/jbc.M413222200] [PMID: 15687497]
[http://dx.doi.org/10.1016/0076-6879(95)48015-3] [PMID: 7674922]
[http://dx.doi.org/10.1016/j.biochi.2010.04.026] [PMID: 20457213]
[http://dx.doi.org/10.1074/jbc.M113.465625] [PMID: 23897806]
[http://dx.doi.org/10.1016/S0006-291X(67)80055-X] [PMID: 6035483]
[http://dx.doi.org/10.1017/S0031182002001828] [PMID: 12166515]
[http://dx.doi.org/10.1186/1471-2091-12-46] [PMID: 21861921]
[http://dx.doi.org/10.1016/S0166-6851(98)00143-1] [PMID: 9879894]
[http://dx.doi.org/10.1099/mic.0.26518-0] [PMID: 14663077]
[http://dx.doi.org/10.1021/bi7022333] [PMID: 18416562]
[http://dx.doi.org/10.2174/092986707780059571] [PMID: 17346152]
[http://dx.doi.org/10.1016/0005-2744(73)90083-1] [PMID: 4750768]
[http://dx.doi.org/10.1517/14728222.11.2.145] [PMID: 17227231]
[http://dx.doi.org/10.1002/ijc.22528] [PMID: 17266036]
[http://dx.doi.org/10.1002/ijc.2910540122] [PMID: 8097496]
[http://dx.doi.org/10.1073/pnas.0611653104] [PMID: 17360568]
[http://dx.doi.org/10.1002/med.20044] [PMID: 16216010]
[http://dx.doi.org/10.1073/pnas.1105601108] [PMID: 21844374]
[http://dx.doi.org/10.1002/art.10517] [PMID: 12355480]
[http://dx.doi.org/10.1159/000189288] [PMID: 8883027]
[http://dx.doi.org/10.1146/annurev.publhealth.23.100901.140525] [PMID: 11910061]
[http://dx.doi.org/10.1016/j.intimp.2006.07.023] [PMID: 17161346]
[http://dx.doi.org/10.2741/2850] [PMID: 17981718]
[http://dx.doi.org/10.1074/jbc.M605203200] [PMID: 16885166]
[http://dx.doi.org/10.1073/pnas.87.17.6878] [PMID: 2395881]
[http://dx.doi.org/10.1515/BC.2006.191] [PMID: 17132098]
[http://dx.doi.org/10.1074/jbc.M111.309500] [PMID: 22493451]
[http://dx.doi.org/10.1128/JB.183.1.178-188.2001] [PMID: 11114915]
[http://dx.doi.org/10.1093/emboj/16.17.5188] [PMID: 9311979]
[http://dx.doi.org/10.1021/cr0101757] [PMID: 12475202]
[http://dx.doi.org/10.1016/j.micinf.2012.04.013] [PMID: 22613209]
[http://dx.doi.org/10.1016/j.biochi.2019.01.007] [PMID: 30654132]
[http://dx.doi.org/10.1073/pnas.0911813107] [PMID: 20133789]
[http://dx.doi.org/10.1107/S1399004714006245] [PMID: 24914976]
[http://dx.doi.org/10.1016/j.biochi.2015.11.021] [PMID: 26616008]
[http://dx.doi.org/10.1046/j.1432-1327.1999.00548.x] [PMID: 10469136]
[http://dx.doi.org/10.1021/bi00285a010] [PMID: 6615800]
[http://dx.doi.org/10.1016/S0021-9258(19)44474-8] [PMID: 4692835]
[http://dx.doi.org/10.1016/S0021-9258(17)33693-1] [PMID: 1254587]
[http://dx.doi.org/10.1021/bi00523a007] [PMID: 7295698]
[http://dx.doi.org/10.1073/pnas.90.11.5006] [PMID: 8506345]
[http://dx.doi.org/10.1021/bi052069v] [PMID: 16519517]
[http://dx.doi.org/10.1021/bi9003638] [PMID: 19408962]
[http://dx.doi.org/10.1021/bi00084a011] [PMID: 8357796]
[http://dx.doi.org/10.1021/bi00045a021] [PMID: 7578088]
[http://dx.doi.org/10.1073/pnas.96.20.11151] [PMID: 10500145]
[http://dx.doi.org/10.1007/s00775-011-0843-2] [PMID: 21918843]
[http://dx.doi.org/10.1016/S0021-9258(18)62858-3] [PMID: 4917241]
[http://dx.doi.org/10.1046/j.1432-1327.2000.01116.x] [PMID: 10672029]
[http://dx.doi.org/10.1046/j.1432-1327.2002.02795.x] [PMID: 11895433]
[http://dx.doi.org/10.1126/science.282.5392.1324] [PMID: 9812898]
[http://dx.doi.org/10.1186/1472-6807-7-84] [PMID: 18093325]
[http://dx.doi.org/10.1016/S0167-4838(99)00271-X] [PMID: 10708856]
[http://dx.doi.org/10.1016/S0898-6568(96)00100-3] [PMID: 9067626]
[http://dx.doi.org/10.1007/s00018-004-3466-8] [PMID: 15197470]
[http://dx.doi.org/10.1016/j.chembiol.2009.01.006] [PMID: 19246010]
[http://dx.doi.org/10.1073/pnas.86.21.8247] [PMID: 2682640]
[http://dx.doi.org/10.1021/bi051691k] [PMID: 16274222]
[http://dx.doi.org/10.1007/BF02256576] [PMID: 11810023]
[http://dx.doi.org/10.1016/S0968-0004(98)01227-4] [PMID: 9697417]
[http://dx.doi.org/10.1016/j.molbiopara.2009.07.008] [PMID: 19660503]
[http://dx.doi.org/10.1021/bi701127x] [PMID: 17929833]
[http://dx.doi.org/10.2174/1389450111009011439] [PMID: 20583970]
[http://dx.doi.org/10.1016/S0021-9258(19)47108-1] [PMID: 2511207]
[http://dx.doi.org/10.1007/s00253-016-7470-3] [PMID: 27023914]
[http://dx.doi.org/10.1186/1471-2091-12-35] [PMID: 21729287]
[http://dx.doi.org/10.1006/bbrc.1998.9056] [PMID: 9705841]
[http://dx.doi.org/10.1021/bi9925827] [PMID: 10736182]
[http://dx.doi.org/10.1021/bi010806r] [PMID: 11524009]
[http://dx.doi.org/10.1021/bi020138p] [PMID: 12044150]
[http://dx.doi.org/10.1016/j.biochi.2015.04.012] [PMID: 25921435]
[http://dx.doi.org/10.1021/jm400395p] [PMID: 23767698]
[http://dx.doi.org/10.1128/jb.171.7.4071-4072.1989] [PMID: 2544569]
[http://dx.doi.org/10.1073/pnas.92.26.12357] [PMID: 8618900]
[http://dx.doi.org/10.1016/j.bmcl.2014.09.047] [PMID: 25293447]
[http://dx.doi.org/10.17843/rpmesp.2015.321.1588] [PMID: 26102119]
[http://dx.doi.org/10.1186/2047-783X-15-12-571] [PMID: 21163732]
[http://dx.doi.org/10.2147/IDR.S30043] [PMID: 22570555]
[http://dx.doi.org/10.1128/CMR.00030-10] [PMID: 21233508]
[http://dx.doi.org/10.1111/j.1432-1033.1975.tb21009.x] [PMID: 1107039]
[http://dx.doi.org/10.1146/annurev.genet.30.1.465] [PMID: 8982462]
[http://dx.doi.org/10.1016/0378-1119(86)90366-5] [PMID: 2436977]
[http://dx.doi.org/10.1073/pnas.0606167103] [PMID: 16938892]
[http://dx.doi.org/10.1016/j.pep.2005.11.012] [PMID: 16380266]
[http://dx.doi.org/10.1016/0003-9861(82)90564-1] [PMID: 7041825]
[http://dx.doi.org/10.1074/jbc.M207926200] [PMID: 12482750]
[http://dx.doi.org/10.2174/1389450115666141024115641] [PMID: 25341419]
[http://dx.doi.org/10.1002/cmdc.201402140] [PMID: 24989844]
[http://dx.doi.org/10.1016/j.ejmech.2018.11.074] [PMID: 30544037]
[http://dx.doi.org/10.1002/pro.2653] [PMID: 25644575]
[http://dx.doi.org/10.1016/j.biochi.2009.06.002] [PMID: 19527767]
[http://dx.doi.org/10.1002/pro.2060] [PMID: 22411732]
[http://dx.doi.org/10.3390/molecules23102607] [PMID: 30314342]
[http://dx.doi.org/10.1128/jb.163.3.1191-1195.1985] [PMID: 2863254]
[http://dx.doi.org/10.1016/j.micres.2012.06.003] [PMID: 22766257]
[http://dx.doi.org/10.1128/JB.01956-07] [PMID: 18223070]
[http://dx.doi.org/10.1107/S1744309106021567] [PMID: 16820698]
[http://dx.doi.org/10.1111/j.1432-1033.1977.tb11952.x] [PMID: 340221]
[http://dx.doi.org/10.1111/j.1432-1033.1975.tb21011.x] [PMID: 1271]
[http://dx.doi.org/10.1016/j.pep.2014.08.002] [PMID: 25123643]
[http://dx.doi.org/10.1016/j.bmcl.2005.08.055] [PMID: 16168644]
[http://dx.doi.org/10.1016/S0960-894X(99)00219-X] [PMID: 10386926]
[http://dx.doi.org/10.1002/prot.25301] [PMID: 28383176]
[http://dx.doi.org/10.7164/antibiotics.29.97] [PMID: 931798]
[http://dx.doi.org/10.7164/antibiotics.29.600] [PMID: 956051]
[http://dx.doi.org/10.1021/jm00214a010] [PMID: 850237]
[http://dx.doi.org/10.2174/1389200013338748] [PMID: 11465152]
[http://dx.doi.org/10.2174/1568011053765949] [PMID: 15992355]
[http://dx.doi.org/10.1016/S0021-9258(17)38851-8] [PMID: 2865258]
[http://dx.doi.org/10.1107/S090744490901779X] [PMID: 19622865]
[http://dx.doi.org/10.1902/jop.2001.72.6.714] [PMID: 11453232]
[http://dx.doi.org/10.1016/j.bmcl.2008.09.021] [PMID: 18823778]
[http://dx.doi.org/10.1271/bbb.65.1549] [PMID: 11515538]
[http://dx.doi.org/10.1016/j.bbrc.2010.03.142] [PMID: 20350528]
[http://dx.doi.org/10.1093/emboj/18.16.4513] [PMID: 10449417]
[http://dx.doi.org/10.1006/jmbi.2000.4067] [PMID: 10970742]
[http://dx.doi.org/10.1111/j.1365-2958.2005.04716.x] [PMID: 16091035]
[http://dx.doi.org/10.1093/nar/gkn1078] [PMID: 19136463]
[http://dx.doi.org/10.1002/1873-3468.12224] [PMID: 27213286]
[http://dx.doi.org/10.1038/msb4100050]
[http://dx.doi.org/10.1006/jmbi.1995.0385] [PMID: 7616564]
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb03547.x] [PMID: 2670557]
[http://dx.doi.org/10.1111/j.1365-2958.1994.tb01013.x] [PMID: 8057849]
[http://dx.doi.org/10.1128/jb.135.2.603-611.1978] [PMID: 355237]
[http://dx.doi.org/10.1128/jb.175.18.6038-6040.1993] [PMID: 8104180]
[http://dx.doi.org/10.1016/S1381-1177(98)00116-7]
[http://dx.doi.org/10.1128/JB.183.4.1489-1490.2001] [PMID: 11157967]
[http://dx.doi.org/10.1099/00221287-147-8-2045] [PMID: 11495983]
[http://dx.doi.org/10.1128/JB.182.12.3383-3393.2000] [PMID: 10852868]
[http://dx.doi.org/10.1126/science.287.5462.2391a] [PMID: 10766610]
[http://dx.doi.org/10.1590/S0074-02762006000700001] [PMID: 17160276]
[http://dx.doi.org/10.1164/rccm.201006-0963PP] [PMID: 21075901]
[http://dx.doi.org/10.1038/srep23089] [PMID: 26980157]
[http://dx.doi.org/10.1038/nri3259] [PMID: 22790178]
[http://dx.doi.org/10.1038/35021074] [PMID: 10963599]
[http://dx.doi.org/10.3389/fmicb.2017.00504] [PMID: 28396657]
[http://dx.doi.org/10.1016/j.ijid.2012.01.009] [PMID: 22410279]
[http://dx.doi.org/10.1645/15-745.1] [PMID: 26057618]
[http://dx.doi.org/10.1038/nm.1795] [PMID: 18641659]
[http://dx.doi.org/10.1016/j.chom.2011.07.004] [PMID: 21843872]
[http://dx.doi.org/10.1038/nrmicro2836] [PMID: 22796883]
[http://dx.doi.org/10.1016/j.chembiol.2009.12.014] [PMID: 20142044]
[http://dx.doi.org/10.1007/s11010-012-1260-8] [PMID: 22466806]
[http://dx.doi.org/10.1007/s00284-009-9470-3] [PMID: 19688379]
[http://dx.doi.org/10.1021/bi0501176] [PMID: 15882055]
[http://dx.doi.org/10.1242/jcs.114.7.1253] [PMID: 11256992]
[http://dx.doi.org/10.1021/bi9620969] [PMID: 8961927]
[http://dx.doi.org/10.1016/S1472-9792(09)70013-7] [PMID: 20006307]
[http://dx.doi.org/10.1016/0003-9861(71)90215-3] [PMID: 5561749]
[http://dx.doi.org/10.1021/jm0300532] [PMID: 12801227]
[http://dx.doi.org/10.1016/S0022-2836(03)00862-3] [PMID: 12946343]
[http://dx.doi.org/10.1016/j.bmcl.2005.05.055] [PMID: 15993057]
[http://dx.doi.org/10.1002/anie.200600757] [PMID: 16724298]
[http://dx.doi.org/10.1016/j.tube.2011.10.012] [PMID: 22115541]
[http://dx.doi.org/10.1016/j.bmc.2012.05.022] [PMID: 22704656]
[http://dx.doi.org/10.1039/c2md20096a]
[http://dx.doi.org/10.1016/j.tube.2012.06.001] [PMID: 22765970]
[http://dx.doi.org/10.1021/jm3008695] [PMID: 22913487]
[http://dx.doi.org/10.1016/j.tube.2016.09.025] [PMID: 27856197]
[http://dx.doi.org/10.1016/j.bmcl.2010.03.067] [PMID: 20363127]
[http://dx.doi.org/10.1021/jm901624n] [PMID: 20038112]
[http://dx.doi.org/10.1110/ps.062278006] [PMID: 16823043]
[http://dx.doi.org/10.1073/pnas.0608389103] [PMID: 17114291]
[http://dx.doi.org/10.1016/j.ejmech.2011.11.017] [PMID: 22118830]
[http://dx.doi.org/10.1002/prot.340090107] [PMID: 2017436]
[http://dx.doi.org/10.1093/nar/gkp410] [PMID: 19465397]
[http://dx.doi.org/10.1515/hsz-2012-0308] [PMID: 23241672]
[http://dx.doi.org/10.1046/j.1365-2958.1998.01075.x] [PMID: 9791183]
[http://dx.doi.org/10.1128/IAI.69.1.159-169.2001] [PMID: 11119502]
[http://dx.doi.org/10.1099/mic.0.26634-0] [PMID: 14702415]
[http://dx.doi.org/10.1007/978-1-4419-8414-2_1]
[http://dx.doi.org/10.1111/febs.14009] [PMID: 28075056]
[http://dx.doi.org/10.1089/ars.2006.8.753] [PMID: 16771667]
[http://dx.doi.org/10.1111/j.1365-2958.2009.06760.x] [PMID: 19508281]
[http://dx.doi.org/10.1038/nchembio.189] [PMID: 19578333]
[http://dx.doi.org/10.1515/hsz-2012-0167] [PMID: 22944686]
[http://dx.doi.org/10.1042/bj20031336] [PMID: 14583094]
[http://dx.doi.org/10.1016/S1526-0550(02)00003-3] [PMID: 12297059]
[http://dx.doi.org/10.1016/S0140-6736(01)05321-1] [PMID: 11463434]
[http://dx.doi.org/10.1126/science.284.5418.1318] [PMID: 10334980]
[http://dx.doi.org/10.1128/AAC.01264-08] [PMID: 19188376]
[http://dx.doi.org/10.1128/JB.183.15.4674-4679.2001] [PMID: 11443106]
[http://dx.doi.org/10.1128/JB.183.18.5395-5401.2001] [PMID: 11514525]
[http://dx.doi.org/10.1128/iai.56.4.726-728.1988] [PMID: 3346072]
[http://dx.doi.org/10.1177/10454411010120050301] [PMID: 12002822]
[http://dx.doi.org/10.1111/j.1600-0757.2005.00113.x] [PMID: 15853938]
[http://dx.doi.org/10.1902/jop.2007.060473] [PMID: 17760541]
[http://dx.doi.org/10.1902/jop.1970.41.11.644] [PMID: 4320450]
[http://dx.doi.org/10.1902/jop.1973.44.7.390] [PMID: 4514569]
[http://dx.doi.org/10.1074/jbc.M801034200] [PMID: 18482986]
[http://dx.doi.org/10.1073/pnas.0307639101] [PMID: 15064399]
[http://dx.doi.org/10.1128/IAI.70.3.1113-1120.2002] [PMID: 11854190]
[http://dx.doi.org/10.1515/BC.2003.023] [PMID: 12675513]
[http://dx.doi.org/10.1111/j.1399-302X.1994.tb00074.x] [PMID: 7808772]
[http://dx.doi.org/10.1111/j.1600-0765.1995.tb01292.x] [PMID: 8544102]
[http://dx.doi.org/10.1007/s10541-005-0248-3] [PMID: 16336178]
[http://dx.doi.org/10.1074/jbc.M202779200] [PMID: 12006595]
[http://dx.doi.org/10.1099/mic.0.27767-0] [PMID: 15942008]
[http://dx.doi.org/10.1097/00001574-199501001-00006]
[http://dx.doi.org/10.1053/gast.1996.v110.pm8613015] [PMID: 8613015]
[PMID: 8903587]
[http://dx.doi.org/10.1046/j.1365-2036.2002.01169.x] [PMID: 11860399]
[http://dx.doi.org/10.1073/pnas.241517298] [PMID: 11717398]
[http://dx.doi.org/10.1038/41483] [PMID: 9252185]
[http://dx.doi.org/10.1038/16495] [PMID: 9923682]
[http://dx.doi.org/10.1073/pnas.88.16.6916] [PMID: 1871107]
[http://dx.doi.org/10.1016/j.jmb.2010.03.042] [PMID: 20359484]
[http://dx.doi.org/10.1007/s12275-008-0266-0] [PMID: 19763424]
[http://dx.doi.org/10.1128/AAC.01449-08] [PMID: 19223619]
[http://dx.doi.org/10.1016/S0960-894X(03)00547-X] [PMID: 12873498]
[http://dx.doi.org/10.1099/00221287-140-10-2649] [PMID: 8000535]
[http://dx.doi.org/10.1128/MMBR.63.3.675-707.1999] [PMID: 10477312]
[http://dx.doi.org/10.1371/journal.ppat.1000284] [PMID: 19158962]
[http://dx.doi.org/10.1111/j.1365-2958.2007.05661.x] [PMID: 17381553]
[http://dx.doi.org/10.1111/j.1574-6976.1996.tb00247.x] [PMID: 8703509]
[http://dx.doi.org/10.2471/BLT.11.093427] [PMID: 22461716]
[http://dx.doi.org/10.1097/QCO.0b013e32834a88af] [PMID: 21799407]
[http://dx.doi.org/10.1128/microbiolspec.VMBF-0015-2015] [PMID: 27227302]
[http://dx.doi.org/10.1128/iai.64.11.4495-4500.1996] [PMID: 8890197]
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