Dal on
T ansac ions
FRONTIER
Ci e his: Dal on T ans., 2025, 54,
6778
Recei ed 18 h Feb ua y 2025,
Accep ed 30 h Ma ch 2025
DOI: 10.1039/d5d 00400d
sc.li/dal on
Chi ali y in me al-based an imic obial agen s:
a g owing on ie in biomedical esea ch
F ancisco Mon illa, * Ca los J. Ca asco and Agus ín Galindo
Chi ali y is inc easingly being ecognised as a aluable ool in he design o no el me al complexes aimed
a comba ing an imic obial esis ance. Chi al me al complexes possess unique spa ial configu a ions ha
enable selec i e in e ac ions wi h biological a ge s, p o iding inno a i e solu ions o ea ing diseases
such as cance and an imic obial- esis an in ec ions. Al hough he ela ionship be ween he chi ali y o
me al complexes and hei an imic obial ac i i y was ini ially highligh ed by Dwye and collabo a o s in a
seminal mid-20 h-cen u y s udy, subsequen esea ch explo ing his in iguing ela ionship has been
limi ed. The ew documen ed cases o enan iome -dependen biocidal ac i i y a e mainly limi ed o a
se ies o chi al sil e complexes ecen ly in es iga ed by ou g oup and he Nomiya esea ch eam, which
demons a e enhanced an imic obial efficacy o specific enan iome s.
In oduc ion
An imic obial esis ance (AMR) is a global heal h c isis, o en
e e ed o as a “silen pandemic”.
1–3
AMR occu s when mic o-
o ganisms, including bac e ia,
4
i uses, ungi,
5
and pa asi es,
e ol e o esis he effec s o an imic obial d ugs, making ea -
men s ineffec i e. Se e al ac o s ha e con ibu ed o he apid
de elopmen and sp ead o an imic obial esis ance, including
(i) a lack o public awa eness abou an ibio ics, esul ing in
o e use o misuse o an ibio ics, (ii) he misuse o an ibio ics
o imp o e p oduc ion in he li es ock sec o , (iii) he na u al
p ocess o e olu ion o bac e ial esis ance o an ibio ics, and
(i ) he low in e es in an ibio ic de elopmen wi hin he
pha maceu ical indus y. The e o e, a majo cu en challenge
o public heal h is he de elopmen and implemen a ion o
new effec i e s a egies o educe he eme gence and sp ead o
an imic obial esis ance. In his sense, ino ganic medicinal
chemis y can offe an al e na i e app oach o cu en ea -
men s based on con en ional o ganic d ugs h ough he
design o he apies wi h he abili y o a ge diffe en bio-
chemical pa hways. Me al-based agen s, pa icula ly in he
ields o an imic obial and an icance esea ch, ep esen a
apidly g owing a ea o s udy wi h immense po en ial o
add ess some o he mos p essing challenges in mode n
medicine. These compounds le e age he unique spa ial
a angemen s o hei ligands o me al cen es o selec i ely
in e ac wi h biological a ge s, offe ing inno a i e solu ions
o comba ing diseases such as cance and an imic obial-
esis an in ec ions.
6
Al hough he mechanisms o ac ion o con en ional
o ganic an ibio ics a e e y a ied,
7
i is impo an o highligh
ha he e a e a signi ican numbe o hem ha equi e me al
ions o hei co ec biological ac i i y, such as bleomycin,
which ope a es h ough an Fe(II)-dependen DNA clea age
mechanism, o baci acin, which ac s by dis up ing cell wall
syn hesis ia Zn(II) coo dina ion.
8
The e m “me alloan ibio ic”
has been coined o desc ibe hese me al ion-dependen an i-
bio ics, whose bioac i i y is ca ied ou h ough in e ac ions
wi h a a ie y o biomolecules, including DNA, RNA, p o eins,
lipids and ecep o s. The meaning o he e m “me alloan i-
bio ic”has ecen ly expanded o include, mo e gene ally, all
me al complexes ha exhibi an ibac e ial abili y. Addi ionally,
he inco po a ion o chi ali y in o hese me alloan ibio ics
could u he enhance hei po en ial, as chi al compounds
can exhibi enan iome -speci ic in e ac ions wi h biological
a ge s, po en ially o e coming esis ance mechanisms.
Chi ali y, he geome ic p ope y o molecules ha a e non-
supe imposable on hei mi o images, is a undamen al
concep in chemis y and biology. Chi ali y is also an impo -
an ool in mode n d ug de elopmen , since molecula eco-
gni ion o chi al biological a ge s can p o ide insigh in o he
design o new ac i e d ugs. Thus, d ugs de i ed om na u al
sou ces, ei he di ec ly o a e labo a o y modi ica ion, a e
usually ound only as a single enan iome a he han as a
acema e. In con as , syn he ic chi al d ugs a e ypically p o-
duced in hei acemic o m, which in ol es chemical was e
gene a ion due o syn hesising and adminis e ing an enan io-
me (dis ome ) ha does no ul ill i s in ended pu pose, and
some imes he p esence o he dis ome in a acemic mix u e
Depa amen o de Química Ino gánica, Uni e sidad de Se illa, 41012 Se illa, Spain.
E-mail: [email p o ec ed]
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impai s he body’s abili y o p ope ly u ilise he eu ome o
e en has undesi able pha macological effec s. A no able
example is halidomide, a seda i e d ug ha was eleased in
Eu ope in 1956 bu wi hd awn om he ma ke in he 1960s
due o he e a ogenic effec s o he dis ome ic isome .
9
In he con ex o me al-based d ugs, chi ali y has eme ged
as a c i ical ac o in luencing hei biological ac i i y, selec i-
i y, and he apeu ic efficacy. Chi al me al-based agen s, pa -
icula ly in he ields o an imic obial and an icance esea ch,
ep esen a apidly g owing a ea o s udy wi h immense po en-
ial o add ess some o he mos p essing challenges in
mode n medicine. Chi al con igu a ions can in luence he
pha macodynamic, pha macokine ic, and oxicological p o-
pe ies o d ugs, o en leading o enan iome -dependen bio-
logical beha iou .
Chi ali y in me al coo dina ion complexes can mani es in
h ee main ways: (1) chi al-a -me al complexes h ough an
asymme ic a angemen o ligands a ound he me al cen e ,
which is commonly obse ed in oc ahed al and e ahed al
complexes,
10–12
(2) he common me al-plus-chi al-ligand
app oach in which he p esence o a chi al ligand ans e s he
chi ali y o he complex,
13
and mo e ecen ly (3) by he exis -
ence o a opisome ism due o hinde ed o a ion a ound a
linea L–M–L bond.
14
In he ield o cance esea ch, chi ali y has p o en o be a
decisi e ac o in de e mining he efficacy o me al-based
d ugs.
15–21
This can be exempli ied by oxalipla in,
19
a pla i-
num-based an icance d ug con aining he chi al ligand (R,R)-
cyclohexane-1,2-diamine. Oxalipla in exhibi s signi ican ly
highe biological ac i i y han i s enan iome wi h he (S,S)-
con igu a ion, unde sco ing he impo ance o chi ali y in
d ug design. In con as , he po en ial o enan iome ically
pu e me al complexes as an imic obial agen s has ha dly been
explo ed, despi e ea ly wo k in he middle o he las cen u y
by Dwye e al., in which a chi ali y–biocidal ac i i y ela ion-
ship was demons a ed.
22
To he bes o ou knowledge, he e a e ew examples
epo ed in he li e a u e in which he chi ali y–bac e icidal
ac i i y ela ionship o chi al me alloan ibio ics is s udied.
Examples a e limi ed o some Ru,
23,24
Cu,
25
Au
26
and, mos e-
quen ly, Ag complexes, among which a e ou ecen s udies,
which will be desc ibed in mo e de ail below.
An imic obial p ope ies o chi al sil e
complexes
In ecen yea s, we ha e been in e es ed in he use o ionic
liquids, based on he imidazolium moie y, as sol en s in
homogeneous ca alysis.
27–29
Fo his eason, he epo o
amino acid-based ionic liquids, whe ein hose de i ed om
he D-enan iome ic amino acid exhibi ed supe io an ibac e ial
p ope ies in compa ison wi h hei L-enan iome coun e pa ,
ga ne ed ou in e es .
30
Subsequen ly, we became in e es ed in
he use o chi al amino acid-de i ed imidazolium ca boxyla e
ligands as chi al induc o s in molybdenum asymme ic
ca alysis
31,32
o , al e na i ely, as ligands in coo dina ion poly-
me s o zinc, coppe and sil e .
33,34
The ex ension o his
esea ch o sil e me al p omp ed us o explo e he an i-
mic obial beha iou o hese complexes and o analyse
whe he he chi ali y o he complex in luences i s biocidal
beha iou , as was p e iously desc ibed o amino acid-based
ionic liquids and poly(ionic liquid) memb anes.
30
The com-
plexes [Ag(L
R
)]
n
(L
R
= 2,2′-(imidazolium-1,3-diyl)di(2-alkylace-
a e), Scheme 1) we e p epa ed by eac ing compounds HL
R
F ancisco Mon illa (Le ), Ca los J. Ca asco (Righ ) and
Agus ín Galindo (Cen e)
F ancisco Mon illa ecei ed his Ph.D. unde he supe ision o
P o . Agus ín Galindo in 1999. He conduc ed pos doc o al esea ch
in Lisbon wi h P o . Manuel Nunes and Te esa A ilés om 2000 o
2002, be o e e u ning o he Uni e si y o Se ille, whe e he is now
a p o esso o ino ganic chemis y. His main esea ch in e es s lie
in he applica ions o ansi ion me al complexes in homogeneous
ca alysis and bioino ganic chemis y.
Ca los J. Ca asco g adua ed in chemis y in 2012 and ob ained
his Ph.D. in 2017 unde he supe ision o P o . Galindo and P o .
Mon illa. Following pos doc o al esea ch a Oei as (Po ugal) in
D a. Royo’s g oup, he ejoined he acul y o chemis y in
Galindo’s g oup whe e he is cu en ly se ing as an assis an p o-
esso . His esea ch in e es s a e cen e ed on he syn hesis, cha ac-
e iza ion, and biological/ca aly ic applica ion o o ganome allic
complexes.
Agus ín Galindo ecei ed his Ph.D. unde he supe ision o
P o . E nes o Ca mona (1986). A e pos doc o al wo k in
Toulouse wi h P o . René Ma hieu and P o . Jean-Pie e Majo al,
he e u ned o he Uni e sidad de Se illa, whe e he eached he
posi ion o p o esso o ino ganic chemis y (2001). His esea ch
in e es s a e ela ed o he chemis y o ansi ion me als, hei use
in homogeneous ca alysis, hei biological applica ions, and he
employmen o compu a ional me hods o a ionalise hei
p ope ies.
Dal on T ansac ions F on ie
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wi h Ag
2
O and hey we e cha ac e ized, in he solid s a e, as
no el one-dimensional o wo-dimensional coo dina ion poly-
me s.
35
The an imic obial beha iou o hese sil e complexes
was in es iga ed e sus G am-nega i e and G am-posi i e bac-
e ia. Howe e , no ac i i y was obse ed agains s ains
S. au eus and S. pseudin e medius (G am-posi i e). In con as ,
ac i i y agains E. coli and P. ae uginosa (G am-nega i e) was
obse ed and was ound o be simila o ha o ela ed sil e
ca boxyla e de i a i es (see selec ed examples in Table 1).
F om he obse ed minimal inhibi o y concen a ion (MIC)
and minimal bac e icidal concen a ion (MBC) alues, he
complexes {Ag[(R,R)-L
R
]}
n
(R = Me,
i
P ) showed be e an i-
mic obial p ope ies o bo h bac e ia han hei (S,S)-enan io-
me s. These eu ome s we e p epa ed wi h p ecu so ligands
ob ained om he non-p o einaceous amino acids D-alanine
and D- aline, espec i ely. This ac con i med he ela ionship
be ween chi ali y and an imic obial beha iou ha we had
hypo hesised. Fu he mo e, he beha iou o {Ag[(R,R)-L
iP
]}
n
as a eu ome was suppo ed by i s impac on he o ma ion o
bio ilms, a signi ican i ulence ac o in bac e ia ha mus be
conside ed. This complex was capable o inhibi ing bio ilm
o ma ion a a concen a ion ha was lowe han he MIC in
E. coli assays, while o P. ae uginosa, i was necessa y o each
he MIC o achie e his inhibi ion. The efficacy o he complex
in inhibi ing bac e ial g ow h and bio ilm o ma ion was
u he subs an ia ed by scanning elec on mic oscopy (SEM).
A he MIC alue, signi ican de o ma ion and damage o he
bac e ial walls we e obse ed, indica ing he po en inhibi o y
effec o he complex. Be o e ou s udy, Nomiya’s esea ch
g oup ca ied ou a sys ema ic s udy o sil e complexes wi h
amino acids and ca boxyla es as ligands.
36–43
Conce ning
chi al de i a i es, he esea che s examined he beha iou o
se e al pai s o enan iome s, as de ailed in Table 1. I should
be no ed ha al hough dispa i ies in he an imic obial ac i i-
ies o he wo enan iome s we e disce ned, his obse a ion
was no explici ly accen ua ed in any o he s udies.
In addi ion o ca boxyla es as ligands, one o he mos
s udied amilies o sil e complexes wi h espec o hei bioci-
dal ac i i y has been ha o N-he e ocyclic ca bene (NHC)
ligands.
44–46
Fo his eason, ou esea ch was ex ended o he
p epa a ion o sil e complexes o his na u e ob ained om
chi al amino acids. The aim was o ob ain u he con i -
ma ion o he imp o ed ac i i y agains bac e ia ha one o he
enan iome s migh exhibi . Complexes {Ag[NHC
Mes,R
]}
n
we e
p epa ed by he eac ion o he speci ic imidazolium p ecu so
compound wi h Ag
2
O.
47
These compounds we e cha ac e ised,
in he solid s a e, as one-dimensional coo dina ion polyme s,
in which he sil e ion is bonded o he ca bon a om o he
NHC ligand and o he ca boxyla e g oup o a symme y-
ela ed ca bene ligand (Scheme 1). The an imic obial p o-
pe ies o hese complexes we e e alua ed e sus G am-nega i e
bac e ia, E. coli and P. ae uginosa. Howe e , he complexes did
no demons a e signi ican biocidal ac i i y agains G am-
posi i e s ains S. au eus and S. pseudin e medius. F om he
obse ed MIC and MBC alues, i was ound ha he complex
{Ag[(R)-NHC
Mes,Me
]}
n
exhibi ed he mos effec i e an imic obial
p ope ies compa ed o he complexes wi h o he alkyl g oups.
Mo eo e , his complex was he eu ome o bo h bac e ia,
which was p epa ed wi h he p ecu so ligand ob ained om
he non-p o einaceous α-amino acid D-alanine. The MIC and
MBC alues we e signi ican ly supe io o hose o i s (S)-enan-
iome ic pai (Table 1), con i ming he chi ali y–ac i i y
ela ionship. An addi ional s uc u e–an imic obial effec
ela ionship was e ealed by analysing he MIC and MBC
alues o {Ag[NHC
Mes,R
]}
n
complexes. Speci ically, he s udy
Scheme 1 Sil e complexes wi h an imic obial ac i i y in es iga ed by
ou g oup.
35,47,48
Table 1 An imic obial ac i i ies o enan iome ic pai s o sil e (I) com-
plexes e alua ed using minimum inhibi o y concen a ion (MIC; μg
mL
−1
)
a
Complex E. coli S. au eus P. Ae uginosa Re .
{Ag[(S,S)-L
Me
]}
n
32 No ac i e 16 35
{Ag[(R,R)-L
Me
]}
n
32 No ac i e 4 35
{Ag[(S,S)-L
iP
]}
n
64 No ac i e 32 35
{Ag[(R,R)-L
iP
]}
n
32 No ac i e 16 35
{Ag[(S)-NHC
Mes,Me
]}
n
57 No ac i e 57 47
{Ag[(R)-NHC
Mes,Me
]}
n
28 No ac i e 14 47
Na
3
[Ag((S,S)-NHC
iP
)
2
] 189.3 165.2 189.3 48
Na
3
[Ag((R,R)-NHC
iP
)
2
] 141.8 141.8 141.8 48
[Ag(R-o h )]
2
7.9 62.5 15.7 36
[Ag(S-o h )]
2
15.7 31.3 15.7 36
{[Ag(R-Hpy ld)]
2
}
n
15.7 31.3 15.7 37
{[Ag(S-Hpy ld)]
2
}
n
7.9 15.7 7.9 37
{[Ag
2
(R-ca)
2
]}
n
62.5 125 62.5 38
{[Ag
2
(S-ca)
2
]}
n
31.3 250 31.3 38
{[Ag(R-his)]
2
}
n
62.5 15.7 15.7 39
{[Ag(S-his)]
2
}
n
15.7 62.5 15.7 39
[(R)-AgL1] 25 75 —26
[(S)-AgL1] 75 50 —26
[(R)-AgL2] 50 75 —26
[(S)-AgL2] 75 75 —26
a
Ligand abb e ia ions: L
R
= 2,2′-(imidazolium-1,3-diyl)di(2-alkylace-
a e); NHC
Mes,Me
= ca bene o 2-me hyl(3-mesi yl-1H-imidazol-3-ium-1-
yl)ace a e; NHC
iP
= ca bene o 2,2′-(imidazolium-1,3-diyl)di(2-iso-
p opylace a e); Ho h = 5-oxo-2- e ahyd o u anca boxylic acid;
H
2
py ld = 2-py olidone-5-ca boxylic acid; R- and S-Hca = (1R,4S)- and
(1S,4R)-4,7,7- ime hyl-3-oxo-2-oxabicyclo[2.2.1]hep ane-1-ca boxylic
acid; Hhis = his idine; L1 = N-me hyl, N′-(2-hyd oxy-2-phenyle hyl)-imi-
dazol-3-ium-2-yl; L2 = 4,5-dichlo o N-me hyl, N′-(2-hyd oxy-2-pheny-
le hyl)-imidazol-3-ium-2-yl.
F on ie Dal on T ansac ions
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ound ha he an imic obial ac i i y dec eased in p opo ion
o he inc ease in he s e ic p ope ies o he alkyl g oup R in
he complex.
Las yea , we desc ibed he an imic obial p ope ies o a
se ies o anionic bis(ca bene) sil e complexes Na
3
[Ag
(NHC
R
)
2
], whe e NHC
R
is a 2,2′-(imidazol-2-ylidene) dica boxy-
la e- ype N-he e ocyclic ca bene (Scheme 1). Complexes we e
syn hesised by he in e ac ion o imidazolium dica boxyla e
compounds wi h Ag
2
O in he p esence o aqueous sodium
hyd oxide.
48
Al hough hey exhibi somewha diminished an i-
bac e ial ac i i y compa ed o analogous de i a i es (Table 1),
hese complexes demons a e a no able dis inc ion om o he
esul s we analysed. Speci ically, hese complexes exhibi ac i i y
agains a G am-posi i e s ain, S. au eus, in addi ion o he
usual ac i i y obse ed agains G am-nega i e bac e ia, E. coli
and P. ae uginosa. In e es ingly, he compa ison o MIC and
MBC alues o all s ains o he enan iome ic complexes
Na
3
[Ag((S,S)-NHC
iP
)
2
]andNa
3
[Ag((R,R)-NHC
iP
)
2
] con i med he
ela ionship be ween chi ali y and an imic obial ac i i y, as
obse ed in ela ed sil e sys ems. The eu ome o all s ains
was he (R,R)-enan iome , which was de i ed om D- aline and
showed biocidal ac i i y be e han i s (S,S)-pai , de i ed om
L- aline. This esul con i med he connec ion be ween chi ali y
and biocidal ac i i y, sugges ing a possible gene alisa ion o he
chi ali y–an imic obial ac i i y end. This ela ionship was also
highligh ed in he simul aneous epo o NHC sil e complexes
wi h a chi al 2-hyd oxy-2-phenyle hyl subs i uen in he imidazo-
lium ing ([AgL1] and [AgL2] in Table 1).
26
Table 1 p o ides a summa y o he chi al sil e complexes
o which he chi ali y–ac i i y ela ionship has been in es i-
ga ed. In all cases, he chi ali y is ound o eside on an asym-
me ic ca bon a om o he coo dina ed ligand. Al hough
examples o sil e complexes exhibi ing axial chi ali y ha e
been documen ed,
49
and he i s case o chi ali y a he me al
(a opisome ism) has ecen ly been desc ibed,
14
s udies exam-
ining he co ela ion be ween hese o ms o chi ali y and an i-
bac e ial ac i i y emain absen . Fu he s udies a e equi ed
o unde s and he mechanisms o ac ion o sil e complexes
and o de e mine whe he chi ali y in luences hei ou
known in e ac ions wi h bac e ia, which lead o cell dea h: dis-
up ion o cell walls and memb anes, in e ac ion wi h DNA,
in e ac ion wi h o inhibi ion o p o eins and enzymes, and
gene a ion o eac i e oxygen species (ROS).
50
An imic obial p ope ies o chi al
complexes o o he ansi ion me als
While sil e complexes a e well-documen ed examples o com-
plexes wi h an ibac e ial ac i i y, he e a e o he ansi ion
me als ha ha e he po en ial o se e as a aluable sou ce o
new an ibio ics.
2,3
Fo example, F ei e al. highligh ed 30 com-
plexes wi h ac i i y agains G am-posi i e and/o G am-nega-
i e bac e ia con aining Mn, Co, Zn, Ru, Ag, Eu, I and P
me als om 906 me al-con aining compounds ha we e
sc eened o an imic obial ac i i y by he Communi y o Open
An imic obial D ug Disco e y (CO-ADD†).
3
In his sec ion, we
Table 2 An imic obial ac i i ies o enan iome ic pai s o me al complexes e alua ed using minimum inhibi o y concen a ion (MIC; μgmL
−1
)
a
Complex E. coli S. au eus P. ae uginosa O he bac e ia Re .
{Ru[(S,S)-Salen’](dmso)
2
} No ac i e 12.5 —12.5
b
52
{Ru[(R,R)-Salen’](dmso)
2
} No ac i e 12.5 —25
b
52
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
2
}]Cl
4
64 >128 >128 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
2
}]Cl
4
>128 >128 >128 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
5
}]Cl
4
64 128 128 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
5
}]Cl
4
128 128 >128 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
7
}]Cl
4
16 64 64 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
7
}]Cl
4
16 16 128 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
10
}]Cl
4
4832 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
10
}]Cl
4
4464 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
12
}]Cl
4
2216 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
12
}]Cl
4
2116 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
14
}]Cl
4
218 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
14
}]Cl
4
418 —24
ΛΛ-[{Ru(phen)
2
}
2
{µ-bb
16
}]Cl
4
418 —24
ΔΔ-[{Ru(phen)
2
}
2
{µ-bb
16
}]Cl
4
418 —24
Δ-[Ru(phen)
2
(dppz)]Cl
2
32 —— 8
c
23
Λ-[Ru(phen)
2
(dppz)]Cl
2
128 —— 16
c
23
[(R)-AuL1] 75 25 —— 26
[(S)-AuL1] 75 75 —— 26
[(R)-AuL2] 75 75 —— 26
[(S)-AuL2] 100 75 —— 26
a
Ligand abb e ia ions: H
2
Salen’=N,N′-bis[3-(pipe idinome hyl)-5-( e -bu yl) salicylidene]cyclohexane-1,2-diamine. bb
n
= bis[4(4′-me hyl-2,2′-
bipy idyl)]-1,n-alkane, wi h n= 2, 5, 7, 10, 12, 14, 16. dppz = dipy ido[3,2-a:2′,3′-c]phenazine. L1 = N-me hyl, N′-(2-hyd oxy-2-phenyle hyl)-imida-
zol-3-ium-2-yl; L2 = 4,5-dichlo o N-me hyl, N′-(2-hyd oxy-2-phenyle hyl)-imidazol-3-ium-2-yl.
b
Bac e ia: B. sub ilis,B. mega e ium and B. ce eus.
c
Bac e ia: B. sub ilis.
†h ps://db.co-add.o g/
Dal on T ansac ions F on ie
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will p o ide a concise o e iew o chi al complexes whe e he
biocidal ac i i y o he pai o enan iome ic species was in es i-
ga ed. As p e iously men ioned, he seminal s udy by Dwye
e al. was he i s o examine he ela ionship be ween chi ali y
and biocidal ac i i y o mul iple me als, including Ru, Co, Fe,
Ni, and Os.
22
Rega ding he u henium me al, he e a e se e al com-
plexes wi h biological ac i i y,
51
bu he numbe o s udies
abou he biocidal ac i i y o enan iome ic pai s is low. Fo
example, he an imic obial beha iou o u henium(II) com-
plexes wi h a chi al salen ligand was effec i e agains he
g ow h o G am-posi i e bac e ia bu no agains G am-nega-
i e. The enan iome {Ru[(S,S)-Salen’](dmso)
2
} inhibi ed he
g ow h o o ganisms o a g ea e ex en han he (R,R)-enan io-
me o h ee bac e ia (Table 2).
52
Dinuclea u henium(II)
complexes wi h chi ali y a he me al, namely, ΔΔ/ΛΛ-[{Ru
(phen)
2
}
2
{μ-bb
n
}]
4+
(see Table 2, whe e he b idging bb
n
is a
bis[4(4′-me hyl-2,2′-bipy idyl)]-1,n-alkane ligand), we e highly
ac i e in cases whe e he leng h o he hyd oca bon chain o
he b idging ligand was longe .
24
Complexes wi h a sho link
chain o a igid polycyclic a oma ic link ligand showed e y
li le o no ac i i y agains any o he bac e ial s ains. Only
sligh diffe ences in ac i i y we e obse ed be ween some
examples o he ΔΔ and ΛΛ enan iome s (Table 2), sugges ing
ha chi al ecep o s may no be he in acellula a ge o
hese me al complexes.
24
A second example o chi ali y a he
me al was he epo o he an imic obial ac i i y o enan io-
pu e [Ru(phen)
2
dppz]
2+
complexes (dppz = dipy ido[3,2-a:2′,3′-
c]phenazine, Table 2) on G am-nega i e E. coli and G am-posi-
i e B. sub ilis as bac e ial models. The Δ-enan iome showed a
2- old highe bac e icidal effec han he Λ-enan iome .
23
The an ibac e ial ac i i y o (S) and (R) e anuclea com-
plexes [Cu
4
( anPheol)
2
(H anPheol)
2
(CH
3
OH)
2
](NO
3
)
2
, whe e
anPheol is a Schiffbase ligand, was e alua ed in ba ch cul-
u es o G am-posi i e B. sub ilis and G am-nega i e E. coli.
Bo h enan iome s possess compa able g ow h inhibi o y
effec s on he G am-posi i e s ain, bu hey ha e no bac e i-
cidal ac i i y agains E. coli.
25
The an ibac e ial ac i i ies o he gold enan iopu e com-
plexes [AuL1] and [AuL2] we e also s udied, which ha e he
same o mula as he sil e de i a i es shown in Table 1. The
mos ac i e compound agains S. au eus was he complex [(R)-
AuL1], which exhibi ed a highe MIC alue han i s (S)-enan io-
me and he sil e de i a i es (Table 2).
26
Conclusions and u u e p ospec s
The g owing issue o AMR ep esen s a o midable challenge
o global heal h and equi es inno a i e app oaches o de elop
effec i e ea men s. The explo a ion o me al-based agen s,
pa icula ly hose ha inco po a e chi ali y, offe s a p omising
chance o add essing his c isis. Chi al me al complexes, wi h
hei unique spa ial con igu a ions, ha e demons a ed he
po en ial o selec i ely in e ac wi h biological a ge s, he eby
enhancing hei an imic obial efficacy. The ela ionship
be ween chi ali y and an imic obial ac i i y, al hough ecog-
nised in ea ly s udies, emains unde explo ed, highligh ing a
signi ican oppo uni y o u u e esea ch.
Recen s udies on chi al sil e complexes ha e p o ided
compelling e idence o he enhanced an imic obial p o-
pe ies o speci ic enan iome s. These indings unde sco e he
impo ance o chi ali y in he design o new an imic obial
agen s and sugges ha u he in es iga ion o o he me al-
based chi al complexes could yield aluable insigh s. The
de elopmen o chi al me alloan ibio ics, aking ad an age o
he p inciples o ino ganic medicinal chemis y, could lead o
no el he apies capable o o e coming cu en esis ance
mechanisms.
Fu u e esea ch should ocus on expanding he lib a y o
chi al me al complexes and sys ema ically s udying hei an i-
mic obial p ope ies. This includes explo ing diffe en me als,
ligands, and chi al con igu a ions o iden i y he mos effec i e
combina ions. Addi ionally, unde s anding he mechanisms
by which chi ali y in luences an imic obial ac i i y will be
c ucial in op imising hese compounds o clinical use.
In eg a ing ad anced echniques such as high- h oughpu
sc eening, compu a ional modelling, and s uc u al biology
will be c i ical o accele a ing he disco e y and de elopmen
o new chi al me alloan ibio ics. Collabo a ion be ween che-
mis s, mic obiologis s, and pha macologis s will be essen ial
o ansla ing hese indings in o p ac ical ea men s.
In conclusion, he s a egic inco po a ion o chi ali y in o
me al-based an imic obial agen s ep esen s a p omising on-
ie in he igh agains AMR. By con inuing o explo e and
unde s and he complex in e play be ween chi ali y and bio-
logical ac i i y, we can de elop inno a i e solu ions o one o
he mos p essing challenges in mode n medicine.
Au ho con ibu ions
The au ho s con ibu ed equally o he in es iga ion, da a cu a-
ion, and w i ing –o iginal d a p epa a ion, e iew and
edi ing.
Da a a ailabili y
No new da a we e gene a ed as pa o his a icle.
Conflic s o in e es
The e a e no con lic s o decla e.
Acknowledgemen s
This esea ch was unded by Minis e io de Ciencia e
Inno ación, PGC2018-093443-B-I00, Uni e si y o Se illa (VI
Plan P opio de In es igación y T ans e encia), and B uke ,
B uke –Uni e si y o Se illa awa d. C. J. C. hanks PAIDI 2020
F on ie Dal on T ansac ions
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o a esea ch con ac , suppo ed by he Eu opean Social
Fund and he Jun a de Andalucía. The au ho s hank Cen o
de In es igaciones, Tecnología e Inno ación (CITIUS) o he
Uni e si y o Se illa o p o iding se e al esea ch se ices and
Cen o de Se icios de In o má ica y Redes de Comunicaciones
(CSIRC), Uni e sidad de G anada, o p o iding he compu ing
ime.
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