an ibio ics
Re iew
An i-Bio ilm Molecules Ta ge ing Func ional Amyloids
Le icia Ma illa-Cuenca , Alejand o Toledo-A ana and Jaione Valle *


Ci a ion: Ma illa-Cuenca, L.;
Toledo-A ana, A.; Valle, J.
An i-Bio ilm Molecules Ta ge ing
Func ional Amyloids. An ibio ics 2021,
10, 795. h ps://doi.o g/10.3390/
an ibio ics10070795
Academic Edi o : Thee hanka Das
Recei ed: 31 May 2021
Accep ed: 25 June 2021
Published: 29 June 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
Ins i u o de Ag obio ecnología (Idab), CSIC-Gobie no de Na a a, 31192 Na a a, Spain;
[email p o ec ed] (L.M.-C.); [email p o ec ed] (A.T.-A.)
*Co espondence: [email p o ec ed]
Abs ac :
The choice o an e ec i e he apeu ic s a egy in he ea men o bio ilm- ela ed in ec ions
is a signi ican issue. Amyloids, which ha e been his o ically ela ed o human diseases, a e now
conside ed o be p e ailing s uc u al componen s o he bio ilm ma ix in a wide ange o bac e ia.
This assump ion c ea es he po en ial o an exci ing esea ch a ea, in which unc ional amyloids a e
conside ed o be a ac i e a ge s o d ug de elopmen o dissemble bio ilm s uc u es. The p esen
e iew desc ibes he bes -cha ac e ized bac e ial unc ional amyloids and ocuses on an i-bio ilm
agen s ha a ge in insic and acul a i e amyloids. This s udy p o ides a be e unde s anding o he
di e en modes o ac ions o he an i-amyloid molecules o inhibi bio ilm o ma ion. This in o ma ion
can be u he exploi ed o imp o e he he apeu ic s a egies o comba bio ilm- ela ed in ec ions.
Keywo ds: bio ilm; amyloids; an ibio ic esis ance; pep ides; polyphenols
1. In oduc ion
1.1. Bio ilm Rela ed In ec ions
Nosocomial in ec ions ela ed o he use o medical de ices a e associa ed wi h a high
isk o mo ali y and inc eased economic cos s [
1
]. These in ec ions a e mainly caused
by oppo unis ic bac e ia such as
E
n e ococcus aecium,
S
aphylococcus au eus,
K
lebsiella
pneumoniae,
A
cine obac e baumannii,
P
seudomonas ae uginosa, and
E
n e obac e species om
he ESKAPE g oup, many o which a e esis an o commonly used an ibio ics [
2
]. The apid
appea ance o an ibio ic esis ance in hese bac e ia is associa ed wi h a global inc ease in
an ibio ic consump ion in he ields o heal h ca e, ag icul u e, and in he en i onmen ,
in addi ion o hei inapp op ia e u iliza ion ela ed o inadequa e dosing o an ibio ic
selec ion [
3
–
5
]. The di icul y o ea ing heal hca e-associa ed in ec ions is also in ensi ied
by he common ai o he oppo unis ic bac e ia o o m bio ilms. Bac e ia a e able o o m
mul icellula communi ies on he su ace o bioma e ials, mucosa, issues, and sec e ions,
and exp ess a sel -gene a ed ex acellula polyme ic ma ix in esponse o my iad signals.
The ex acellula ma ix, composed o polysaccha ides, su ace p o eins, nucleic acids, and
amyloid ibe s, p o ec s he mic obes om ex e nal insul s and ad e se en i onmen al
condi ions. The bio ilm ma ix ac s as a physical and chemical ba ie ha educes he
a e o an imic obial pene a ion. In addi ion, i can gene a e mic oen i onmen s ha
an agonize he ac ion o an ibio ics and p omo e he abili y o bac e ia o gene a e pe sis e
cells wi h inc eased d ug ole ance [
6
–
9
]. Thus, bac e ia in bio ilms a e less sensi i e
o an ibio ics han he same s ain g owing in suspension, esul ing in a 10- o 100- old
dec ease in hei suscep ibili y [
10
]. Because con en ional an ibio ics ail o success ully
ea bio ilm-associa ed in ec ions, no el he apeu ic solu ions a e in u gen ly needed.
E o s a e cu en ly unde way o de elop new he apeu ic app oaches ha ocus on
p e en ing he syn hesis o he assembly o he bio ilm ma ix componen s o ende
bac e ia sensi i e o an ibio ic ea men s.
An ibio ics 2021,10, 795. h ps://doi.o g/10.3390/an ibio ics10070795 h ps://www.mdpi.com/jou nal/an ibio ics
An ibio ics 2021,10, 795 2 o 18
1.2. Amyloids as S uc u al Sca olds o he Bio ilm Ma ix
Amyloids a e adi ionally associa ed wi h se e al incu able degene a i e human
diseases. Howe e , nume ous s udies ha e indica ed ha mic oo ganisms make use o
amyloidogenic p o eins o a numbe o non-pa hological p ocesses [
11
]. In ecen decades,
amyloids ha e been conside ed o be essen ial componen s o he bio ilm, p o iding con-
sis ency and iscoelas ici y o he ex acellula bio ilm ma ix [
12
–
15
]. Amyloids a e highly
o de ed ib illa p o eins wi h a
β
-shee seconda y s uc u e and a s ongly conse ed
qua e na y c oss-
β
s uc u e [
16
]. To a lesse ex en ,
α
-helices can eplace he
β
-s ands,
hus o ming c oss-
α
ib ils [
17
,
18
]. The amyloid s uc u e binds a ange o speci ic dyes
such as Congo ed, Thio la in T (ThT), and P o eoS a , which, combined wi h o he bio-
physical echniques, such as solid-s a e NMR and Fou ie - ans o m in a ed spec oscopy
(FTIR), a e no mally used o de e mine he amyloidogenic ea u es o a p o ein [
19
–
22
].
Due o he well-o de ed s uc u e o
β
-s ands ha a e aligned pe pendicula o a ib il
axis, amyloids a e an e ec i e ex acellula building ma e ial. They a e mos ly esis an
o ha sh dena u ing condi ions and p o eoly ic clea age. In addi ion, polyme iza ion o
amyloidogenic p o eins occu s h ough a nuclea ion-dependen sel -assembly p ocess, in
which s a e amyloid agg ega es p o ide a con o ma ional sca old ha acili a es he
assembly o polyme ic subuni s in o he amyloid s a e in he absence o ene gy. Due o his
seeding mechanism, he amyloid con o ma ion is sui able unde condi ions in which he
ene gy is limi ed [12,23].
Taking in o accoun ha amyloids a e widely dis ibu ed componen s o he bio ilm
ma ix in many bac e ia, hey can be conside ed excellen a ge s o an i-amyloid d ugs o
educe bio ilm o ma ion. This e iew aims o summa ize he cu en knowledge o he
bac e ial amyloids and he di e en mechanisms o ac ion o he an i-amyloid molecules o
inhibi bio ilm o ma ion.
2. Func ional Amyloids o he Bio ilm Ma ix
In ecen yea s, an inc easing numbe o amyloid componen s o he bio ilm ma ix
ha e been iden i ied, pu i ied, and closely in es iga ed [
15
]. Based on he s uc u al and
unc ional s a e o he amyloidogenic p o eins, i is becoming popula o g oup hem in o
in insic and acul a i e amyloids (Table 1) [24].
2.1. In insic Amyloids
The polyme ic s uc u e o in insic amyloids is he esul o a dedica ed sys em
ha con ols he sec e ion and assembly o he monome ic building blocks. Indeed, he
amyloidogenic subuni s do no ha e a olded s a e p io o o ming he amyloid ibe s. The
amyloid con o ma ion ep esen s he p ima y s uc u al and unc ional s a e o he p o ein.
Examples o amyloids om his g oup a e desc ibed below.
2.1.1. Cu li (csgBAC-csgDEFG Genes)
The cu li imb iae p esen in E. coli,Salmonella, and o he En e obac e ia is one o he
mos well-cha ac e ized unc ional amyloid sys ems. The cu li-speci ic genes a e disposed
in wo di e gen ope ons csgBAC and csgDEFG [
25
]. CsgA is he majo cu li subuni ha
s uc u ally o ms he amyloid ibe s. To achie e his, he mino cu li subuni CsgB ac s as
a nuclea o o CsgA assembly (Figu e 1a). To a oid he o ma ion o oxic oligome s inside
he cell, he pe iplasmic p o ein CsgC ac s as a chape one ha main ains CsgA as a soluble
and uns uc u ed monome , hus p e en ing he amyloid s a e [26]. The csgDEFG ope on
code o p o eins ha a e in ol ed in he egula ion, s abiliza ion, and sec e ion o CsgA
and CsgB subuni s [
26
–
28
]. CsgA and CsgB each he ex acellula milieu, due o a po e-like
s uc u e o med by CsgG in he ou e memb ane [
29
]. The accesso y p o eins CsgF and
CsgE a e associa ed wi h CsgG and con ibu e o he p ope assembly o cu li ibe s [
30
].
In addi ion, CsgF in e ac s wi h CsgB, ensu ing he a achmen o he subuni on he cell
su ace and hus, he ibe o ma ion [
30
]. CsgD con ols a he ansc ip ional le el he
exp ession o he csgBAC ope on [
31
,
32
] which is igge ed by en i onmen al and chemical
An ibio ics 2021,10, 795 3 o 18
signals such as osmolali y, oxygen, and empe a u e [
33
,
34
]. Cu li a e implica ed in su ace
coloniza ion, cell–cell con ac , bio ilm ma ix sca olding, p o ec ion agains an imic obial
agen s and desicca ion. Mo eo e , cu li play an impo an ole in he in e ac ion wi h hos
cell ecep o s and he immune sys em [35–39].
An ibio ics 2021, 10, 795 3 o 17
le el he exp ession o he csgBAC ope on [31,32] which is igge ed by en i onmen al and
chemical signals such as osmolali y, oxygen, and empe a u e [33,34]. Cu li a e implica ed
in su ace coloniza ion, cell–cell con ac , bio ilm ma ix sca olding, p o ec ion agains an-
imic obial agen s and desicca ion. Mo eo e , cu li play an impo an ole in he in e ac-
ion wi h hos cell ecep o s and he immune sys em [35–39].
Figu e 1. Schema ic ep esen a ion o he genes in ol ed in he o ma ion o in insic amyloids, he d ugs a ge ing such
s uc u es and hei mechanism o ac ion. (a) The o ma ion o E. coli and S. Typhimu ium cu li amyloids is a ec ed by
se e al d ugs, which ac by di e en mechanisms: (i) s abiliza ion o CsgA monome ic subuni s; (ii) o ma ion o amo -
phous o non-amyloidogenic agg ega es; (iii) disagg ega ion o al eady- o med ibe s; (i ) p e en ion o CsgB polyme i-
za ion; ( ) solubiliza ion o CsgB; ( i) ac i a ion o he cell su ace s ess esponse, which educes he exp ession o he
cu li egula o CsgD. (b) Pseudomonas Fap amyloids a e inhibi ed by EGCG and PGG polyphenols, which lead FapC o
o -pa hway oligome s, emodeling ibe s in o amo phous agg ega es and e aining quo um-sensing molecules.
Table 1. Classi ica ion o unc ional amyloids.
Amyloid Type
Locus
Amyloid Subuni s
Bac e ia
In insic amyloids
Cu li
csgDEFG; csgBAC
CsgA, CsgB
E. coli, Salmonella
[40]
Fap
apABCDEF
FapC, FapB,
P. ae uginosa
[41]
MTP
m p
MTP
Mycobac e ium ube culosis
[42]
Chaplins/Rodlins
chpA, chpD, dlA, dlB;
chpC, chpH; chpF, chpG;
chpB, chpE
ChpD-H, RdlB
S ep omyces coelicolo
[43,44]
Facul a i e amyloids
PSMs
psmα1–4; psmβ1–2; hld
PSMα, PSMβ, δ- oxin
S. au eus, CNS 1
[17,45]
TasA
apA, sipW, asA
TasA
B. sub ilis, B. ce eus
[46,47]
Bap
bap
BapB-domain
S. au eus, CNS 1
[48]
Esp
esp
N- e minal domain
E. aecalis
[49]
P1
p1
AgII-C123 egion
S. mu ans
[50]
WapA
wapA
WapA
S. mu ans
[51]
SMU_63C
smu_63c
SMU_63C
S. mu ans
[51]
1 CNS: coagulase nega i e s aphylococci.
Figu e 1.
Schema ic ep esen a ion o he genes in ol ed in he o ma ion o in insic amyloids, he d ugs a ge ing such
s uc u es and hei mechanism o ac ion. (
a
) The o ma ion o E. coli and S. Typhimu ium cu li amyloids is a ec ed by
se e al d ugs, which ac by di e en mechanisms: (i) s abiliza ion o CsgA monome ic subuni s; (ii) o ma ion o amo phous
o non-amyloidogenic agg ega es; (iii) disagg ega ion o al eady- o med ibe s; (i ) p e en ion o CsgB polyme iza ion;
( ) solubiliza ion o CsgB; ( i) ac i a ion o he cell su ace s ess esponse, which educes he exp ession o he cu li
egula o CsgD. (
b
)Pseudomonas Fap amyloids a e inhibi ed by EGCG and PGG polyphenols, which lead FapC o o -
pa hway oligome s, emodeling ibe s in o amo phous agg ega es and e aining quo um-sensing molecules.
Table 1. Classi ica ion o unc ional amyloids.
Amyloid Type Locus Amyloid Subuni s Bac e ia
In insic amyloids
Cu li csgDEFG; csgBAC CsgA, CsgB E. coli, Salmonella [40]
Fap apABCDEF FapC, FapB, P. ae uginosa [41]
MTP m p MTP Mycobac e ium
ube culosis [42]
Chaplins/Rodlins chpA, chpD, dlA, dlB; chpC,
chpH; chpF, chpG; chpB, chpE ChpD-H, RdlB S ep omyces coelicolo [43,44]
Facul a i e amyloids
PSMs psmα1–4; psmβ1–2; hld PSMα, PSMβ,δ- oxin S. au eus, CNS 1[17,45]
TasA apA, sipW, asA TasA B. sub ilis, B. ce eus [46,47]
Bap bap BapB-domain S. au eus, CNS 1[48]
Esp esp N- e minal domain E. aecalis [49]
P1 p1 AgII-C123 egion S. mu ans [50]
WapA wapA WapA S. mu ans [51]
SMU_63C smu_63c SMU_63C S. mu ans [51]
1CNS: coagulase nega i e s aphylococci.
An ibio ics 2021,10, 795 4 o 18
2.1.2. Fap ( apA-F Genes)
Fap ibe s a e p oduced by Pseudomonas spp. as pa o he bio ilm ma ix [
52
]. The
Fap ibe machine y is encoded in he ope on apA-F. The Fap ibe s a e assembled by
he majo s uc u al subuni FapC, and he wo mino subuni s FapB and FapE. FapB
is equi ed o ibe polyme iza ion whe eas FapE ac s as an ex acellula chape on-like
p o ein (
Figu e 1b
). The h ee p o eins a e expo ed ou side he cell h ough he po e-
like s uc u e o med by FapF [
53
]. FapA wo ks as a chape one o he ibe monome s
du ing he sec e ion p ocess whe eas FapD, a cys eine p o ease loca ed in he pe iplasm,
is equi ed o FapC ex e naliza ion [
53
]. The assembly o Fap amyloids in he bio ilm
enhances cell agg ega ion and a achmen con e ing p o ec ion agains chemical and
mechanical a ack [
52
]. In addi ion, Fap amyloids inc ease he o e all hyd ophobici y and
s i ness o he bio ilm, hus p e en ing bac e ia desicca ion [54].
2.1.3. Chaplins and Rodlins
Filamen ous bac e ia, such as S ep omyces, g ow abo e humid su aces o ming
b anching hyd ophobic s uc u es called ae ial hyphae ha ul ima ely esul in hyd opho-
bic spo es [
55
]. The amyloidogenic p o eins, chaplins and odlins a e in ol ed in he
o ma ion o hese [
43
,
44
]. The e a e eigh chaplins (ChpA–H) and wo odlins (RdlA and
RdlB). The long chaplins (ChpA–C) ha e a C- e minal so ing signal o a achmen o
he pep idoglycan ia a so ase-media ed co alen bound wi h he LAXTG mo i and wo
chaplin domains ha a e highly hyd ophobic, whe eas he sho chaplins (ChpD-H) ha e
one chaplin domain [
56
]. To da e, because long chaplins canno be ex ac ed om he cell
walls o ae ial hyphae due o he co alen linkage, only sho chaplins ha e been shown
o o m
β
-shee s uc u es and hus amyloid-like ibe s [
57
]. I is he e o e possible ha
ChpA-C se e as ancho ing si es o ChpD-H chaplins o o m amyloid ibe s, and ha
ChpE is esponsible o he coo dina ion o he polyme iza ion o he ibe subuni s in a
high pH-dependen mechanism [
58
]. In addi ion o chaplins, he RodA and RodB odlins
polyme ize in o he hyd ophobic s uc u e known as he odle laye , which co e s he
su ace o ae ial hyphae and spo es. Amyloid chaplins a e aligned in o o de ed odle s by
he ac ion RdlA and RdlB, only he la e is able o o m amyloid ib ils in i o [59].
2.2. Facul a i e Amyloids
The acul a i e amyloids include p o eins wi h a dual unc ion. They a e sec e ed in a
unc ional globula olded s a e ha , unde ce ain condi ions, changes hei con o ma ion
o an amyloid old [
12
,
24
]. Two ypes o acul a i e amyloids can be di e en ia ed. One
ype comp ises sec e ed monome ic p o eins, such as S. au eus phenol-soluble modulins
(PSMs) and Bacillus sub ilis TasA, which assemble in o amyloid ibe s upon con o ma ional
change occu s. The o he g oup includes p o ein domains wi h amyloidogenic ea u es,
which has been p e iously p ocessed om a na i e su ace p o ein (e.g., S. au eus Bap,
En e ococcus aecalis Esp, and S ep ococcus mu ans P1, WapA, and SMU_63C). In hei na i e
con o ma ion, he acul a i e amyloids o he o me g oup can ac as an imic obials and
oxins, whe eas he la e wo k as cell su ace adhesins. Bo h u n in o ma ix sca olds
when hey polyme ize in o amyloid s uc u es.
2.2.1. Phenol-Soluble Modulins (PSMs)
Phenol-soluble modulins (PSMs) a e small alpha-helical amphipa hic pep ides in-
ol ed in he i ulence o S. au eus [
60
,
61
]. S. au eus exp esses ou
α
-PSMs (PSM
α
1–
PSM
α
4) encoded in he
α
-psm ope on, wo
β
-PSMs (PSM
β
1 and PSM
β
2) encoded in he
β
-psm ope on and
γ
-PSM (
δ
- oxin) p oduced om RNAIII, a egula o y RNA o he Ag
sys em [
62
–
64
]. PSMs lack he ypical Sec-signal and hei sec e ion is ca ied ou by an ATP-
binding casse e (ABC) anspo e [
65
]. Once a he ex acellula media, PSMs may ei he
wo k as soluble p o eins ha ing an imic obial and immunomodula ing ac i i ies [
66
–
69
] o
change he con o ma ion and polyme ize in o unc ional amyloids (Figu e 2a). PSM
α
1 and
PSM
α
4 o m agg ega es showing a ypical amyloid c oss-
β
s uc u e [
45
] whe eas PSM
α
3
An ibio ics 2021,10, 795 5 o 18
agg ega es display an unusual c oss-
α
s uc u e [
17
]. This s uc u al polymo phism e eals
di e en bac e ial unc ions. Al hough PSM
α
1 and PSM
α
4 pa icipa e in bio ilm o ma ion,
PSM
α
3 is in ol ed in cy o oxici y o human T cells, p obably due o i s pa icula amyloid
a chi ec u e [17].
An ibio ics 2021, 10, 795 5 o 17
PSMα1 and PSMα4 o m agg ega es showing a ypical amyloid c oss-β s uc u e [45]
whe eas PSMα3 agg ega es display an unusual c oss-α s uc u e [17]. This s uc u al pol-
ymo phism e eals di e en bac e ial unc ions. Al hough PSMα1 and PSMα4 pa icipa e
in bio ilm o ma ion, PSMα3 is in ol ed in cy o oxici y o human T cells, p obably due o
i s pa icula amyloid a chi ec u e [17].
Figu e 2. Schema ic ep esen a ion o he genes in ol ed in he assembly o acul a i e amyloids, he d ugs a ge ing such
s uc u es and hei mechanism o ac ion. (a) D ugs a ge ing S. au eus PSMs ac by se e al mechanisms ha in ol e he
s abiliza ion o PSM -shee s uc u e and ibe disassembly. (b) B. sub ilis TapA polyme iza ion is inhibi ed by AA-861
and pa henolide. (c) The la onoids que ce in, my ice in, and scu ella ein inhibi polyme iza ion o he Bap amyloid ag-
g ega es by s abiliza ion o he Bap p o ein. (d) Polyme iza ion o he amyloids S. mu an s WapA and AgII/C123 is inhib-
i ed by AA-861, Tannic acid (TA), and EGCG and indi ec ly by he AFhPs and P1 pep ides. SMU_63c amyloids a e inhib-
i ed by EGCG.
Figu e 2.
Schema ic ep esen a ion o he genes in ol ed in he assembly o acul a i e amyloids, he d ugs a ge ing such
s uc u es and hei mechanism o ac ion. (
a
) D ugs a ge ing S. au eus PSMs ac by se e al mechanisms ha in ol e he
s abiliza ion o PSM
α
-shee s uc u e and ibe disassembly. (
b
)B. sub ilis TapA polyme iza ion is inhibi ed by AA-861
and pa henolide. (
c
) The la onoids que ce in, my ice in, and scu ella ein inhibi polyme iza ion o he Bap amyloid
agg ega es by s abiliza ion o he Bap p o ein. (
d
) Polyme iza ion o he amyloids S. mu an s WapA and AgII/C123 is
inhibi ed by AA-861, Tannic acid (TA), and EGCG and indi ec ly by he AFhPs and P1 pep ides. SMU_63c amyloids a e
inhibi ed by EGCG.

An ibio ics 2021,10, 795 6 o 18
2.2.2. TasA
The B. sub ilis bio ilm con ains unc ional ibe s wi h amyloidogenic p ope ies. The
main amyloid componen is TasA ( ansloca ion-dependen an imic obial spo e compo-
nen ), which sel -assembles in o amyloid ibe s (Figu e 2b) [
46
]. The accesso y p o ein
TapA (TasA ancho ing and assembly p o ein) assis s in he o ma ion o TasA ib ils on o
he cell su ace [
47
]. SipW is a memb ane-bound pep idase ha clea es he TapA and
TasA signal pep ides be o e sec e ion [
70
]. S uc u al analyses ha e shown ha TasA is
sec e ed in a globula s a e ha ansi s o an amyloid con o ma ion unde en i onmen al
condi ions such as acidic pH and hyd ophobici y [
71
]. In addi ion o i s s uc u al ole in
he mul icellula beha io , TasA main ains he cell memb ane s abili y and p e en s excess
cell dea h unde bio ilm g ow h condi ions [72].
2.2.3. Bio ilm Associa ed P o eins (BAPs)
BAPs a e high molecula weigh p o eins p esen on bac e ial cell su aces and a e
cha ac e ized by a mul i-domain a chi ec u e [73,74]. The pa adigm S. au eus Bap p o ein
is o ganized in se e al domains (Figu e 2c) including a pu a i e Sec-dependen signal
pep ide o hei expo ollowed by a N- e minal domain, which comp ises egion A and B,
he la e ca ies he EF-hand mo i s o calcium binding [
75
,
76
]. The eupon, a co e domain
o med by andem epea s (C egion) and a egion D a he C- e minus, which con ains
he LPXTG mo i o ancho ing he p o ein o he cell wall. Bap o ms amyloid ibe s
unde speci ic en i onmen al ci cums ances [
48
]. Once he p o ein is co alen ly ancho ed
o he pep idoglycan, he N- e minal egion is p ocessed and eleased o he ex acellula
media. As a esul , agmen s o Bap adop an uns able mol en globule-like s a e. When
acidic pH and low concen a ion o Ca
2+
a e ound in he medium, he mol en globule
swi ches o an agg ega ion-p one con o ma ion ha enables sel -assembly in o amyloid
ibe s ha p omo e bio ilm o ma ion (Figu e 2c) [
48
]. In con as , when Ca
2+
is a ailable,
i binds o he EF-hand mo i s, s abilizing Bap in i s na i e olded s a e and impai ing
he polyme iza ion o he amyloid ibe s and bio ilm o ma ion [
48
,
76
]. I is no able ha
Bap ca ies ou addi ional unc ions in i s p ima y globula s a e. I ac s as an adhesin,
p omo ing he p ima y a achmen o S. au eus o abio ic su aces and hus playing an
impo an ole in ini ial s ages o bio ilm o ma ion [
75
]. In addi ion, Bap is in ol ed in
he pa hogenesis o S. au eus by imp o ing he adhesion o epi helial cells o mamma y
glands [
77
] bu exe ing a p o ec i e ole by p e en ing S. au eus en y in o epi helial cell
h ough binding o he Gp96 cell hos ecep o [78].
The
E
n e ococcal
s
u ace
p
o ein (Esp) is a Bap-o hologous p o ein p esen in E.
aecalis [
79
,
80
]. The mul i-domain con igu a ion o Esp is simila o ha o Bap. The Esp
N- e minal domain and he egion C sha e 26% and 23% o iden i y wi h he co esponding
Bap domains, espec i ely [
49
]. Analogously, he Esp N- e minal domain is su icien o
induce bio ilm o ma ion [
81
]. Ou g oup has ecen ly desc ibed he capaci y o he Esp N-
e minal egion o o m amyloid-like ibe s in a pH-dependen manne [
49
]. The simila i ies
obse ed be ween Bap and Esp sugges ha he dual unc ion o amyloid/adhesin may be
widesp ead among membe s o he BAP amily.
2.2.4. P1 Adhesin/WapA/SMU_63c
Ano he example o a su ace-associa ed adhesin wi h amyloidogenic p ope ies is
he P1 p o ein (also known as AgI/II, PAc, SpaP o an igen B) o S. mu ans. This P1 is a
la ge p o ein ha is co alen ly ancho ed o he cell wall h ough i s C- e minal LPXTG
mo i . P1 is able o bind ex acellula p o eins [
82
–
84
]. The e ia y s uc u e is a p olonged
s alk wi h a globula domain ha con ains
β
-shee s. P1 can be p ocessed and i s C- e minal
domain (AgII o C123 agmen ) can be loosely associa ed wi h he co alen ly ancho ed
p o ein (Figu e 2d) [
85
]. The C123/AgII agmen con ains he amyloid- o ming moie y ha
may be implica ed in he o ma ion o ib illa s uc u es wi h amyloid p ope ies [
50
,
86
].
In addi ion, he wall-associa ed p o ein A (WapA) and he sec e ed p o ein SMU_63c
o S. mu ans con ibu e o he ib illa s uc u es depending on he pH [
51
]. As he P1
An ibio ics 2021,10, 795 7 o 18
adhesin, WapA is p ocessed and o ms amyloid ibe s a neu al pH, whe eas SMU_63c
does no need o be p ocessed and o ms amyloid s uc u es a acidic pH. O e all, his
e idence sugges s ha en i onmen al condi ions a e c ucial o he egula ion o S. mu ans
amyloid ibe s.
3. D ugs Ta ge ing Amyloid-S uc u ed Bio ilms
Amyloid ibe s appea o be common bio ilm ma ix elemen s in many pa hogenic
bac e ia. Se e al app oaches ha e been ocused on sea ching o compounds ha ei he
al e he exp ession o he elemen s in ol ed in he amyloid p oduc ion o in e up hei
assembly. The iden i ica ion o he an i-amyloid compounds o disassemble bio ilms has
been ca ied ou by means o high- h oughpu sc eening o ac i e molecule collec ions,
he design o pep ides based on he s uc u al biology o he amyloidogenic segmen s o
he epu posing o molecules designed agains human amyloids. The mos ep esen a i e
d ugs ac i e agains amyloid- ela ed bio ilms and hei mechanisms o ac ion a e discussed
below and shown in Table 2.
Table 2. An i-bio ilm agen s a ge ing bac e ial amyloids.
Type Amyloid Inhibi o s An i-Bio ilm E ec Bac e ial Amyloid
Ta ge
Euka yo ic
Amyloid Ta ge Re e ence
Pep ides
ANK6 S. Typhimu ium CsgA Aβ[87]
DB3DB3 S. Typhimu ium CsgA Aβ[87]
AP90 S. au eus PSMα1 ND [88]
AFhPs
S. mu ans,
S. sanguis,
S. au eus,
E. coli
ND ND [89]
P1 S. mu ans ND ND [89]
P o eins TTR E. coli CsgA Aβ, HepF-N [89]
B. sub ilis ND
An ibodies 3H3 S. Typhimu ium Cu li Aβ, TTR, Tau [90]
Molecula weeze s CLR01 S. au eus PSMα1 Aβ,α-syn, Tau [91]
CLR05 S. au eus PSMα1 Aβ,α-syn, Tau [91]
Cu licides
FN075 E. coli Cu li Aβ[92]
BibC6 E. coli Cu li ND [92]
VA028 E. coli Cu li ND [92]
Bioac i e compounds AA-861
B. sub ilis TasA
New1
[93]
S. mu ans P1
WapA [92]
Pa henolide B. sub ilis TasA New1 [93]
An ibio ics 2021,10, 795 8 o 18
Table 2. Con .
Type Amyloid Inhibi o s An i-Bio ilm E ec Bac e ial Amyloid
Ta ge
Euka yo ic
Amyloid Ta ge Re e ence
Polyphenols
EGCG
E. coli CsgA
CsgB
Aβ,α-syn, Tau
[94]
Pseudomonas sp. FapC [95,96]
S. mu ans
P1
WapA
SMU_63c [89]
S. au eus PSMα1PSMα4 [97]
PGG Pseudomonas sp. FapC Aβ[95]
Tannic acid S. mu ans P1
WapA P ion P P, Aβ[51]
Lu eolin E. coli CsgA Aβ,α-syn [98]
Mo in E. coli CsgA Aβ,α-syn [98]
My ice in E. coli,S. au eus CsgA
Bap Aβ,α-syn [98,99]
Que ce in E. coli CsgA
Bap Aβ,α-syn [98,99]
Phlo e in E. coli CsgA
CsgB Aβ,αSA53T [98]
ND: non de e mined; Aβ: Amyloid β;α-syn: α-synuclein; αSA53T: mu an o m o α-synuclein.
3.1. An i-Amyloid Pep ides
The design o pep ides binding o he domains in ol ed in amyloid ib illa ion is one
o he mos p omising s a egies used o in e up amyloid ma u a ion and consequen ly
bio ilm o ma ion. Based on he s uc u al simila i ies exis ing be ween he amyloidogenic
domains de i ed om CsgA and hose om human amyloids, Pe o and collabo a o s
ound ha he D-enan iome ic pep ides (ANK6 and DB3DB3) inhibi ed he ib illa ion o
CsgA (Table 2) [
87
]. ANK6 and DB3DB3 pep ides we e op imized o hei po en ial o
emo e amyloid-
β
(A
β
) oligome s associa ed wi h Alzheime ’s disease. The D-pep ides
bound o CsgA, hus p omo ing he s abiliza ion o he monome subuni s o inducing he
o ma ion o amo phous agg ega es, which we e unable o assemble in o amyloid ibe s
(Figu e 1a). The pep ides inhibi he ib illa ion o he CsgA spine segmen s con ained
a he R1 and R5 epea s. The inhibi o y ac ion o he pep ides appea s o be speci ic o
he seconda y s uc u e o he p o ein because ANK6 and DB3DB3 do no ha e any e ec
on c oss-
α
amyloid-like ib ils o med by PSM
α
3 ib illa ion [
87
]. This dis inc ion was
u he exempli ied in a pionee ing s udy ha designed pep ides ha we e complemen a y
o he
α
-shee o PSM
α
1. I is o en conside ed ha , because amyloids con ain a c oss-
β
-
s uc u e, he in e media e agg ega i e species mus also con ain a
β
-s uc u e. Howe e ,
his is no he case o se e al amyloids, such as PSM
α
1, which unde go a ansi ion om
α
-helix
→α
-shee
→β
-shee du ing agg ega ion [
88
]. The an i-
α
-shee pep ide AP90 a ge s
he ansi ional
α
-shee s uc u e o PSM
α
1, leading o a educ ion o amyloid ib ils
in i o
(Figu e 2a). Consequen ly, AP90 e ec i ely educes bio ilm o ma ion by S. au eus h ough
he in e ac ion wi h PSMs [88].
Ano he in e es ing s a egy o ea ing mic obial in ec ions is based on he use o
amyloidogenic pep ides de i ed om bac e ial amyloids [
100
]. Syn he ic agg ega ion-
p one pep ides om S aphylococcus epide midis (C30, C29, Hi 1, Hi 50) pene a e bac e ia,
hus causing oxic p o ein agg ega ion o polypep ides in he cy osol, which leads o
bac e ial dea h [
101
]. In e es ingly, agg ega ing pep ides a e oxic o bac e ia, bu no o
human cells. Howe e , u he in es iga ions a e needed o es whe he hese pep ides
An ibio ics 2021,10, 795 9 o 18
may ha e an e ec on p o ein agg ega ion and oxici y in human cells ha exp ess amyloids
such as α-synuclein o Aβ.
Fu he mo e, sho pep ides de i ed om he amyloidogenic agmen C123 o he
adhesin P1 o S. mu ans display s ong an i-bio ilm p ope ies wi h small o no cy o oxic
e ec [
89
]. Simula ed amyloid o ming pep ides p edic ed om C123 ha e been syn-
hesized (AFhPs). AFhPs inhibi bio ilm o ma ion in a wide ange o mic oo ganisms
including G am-posi i e and G am-nega i e bac e ia and ungi. These pep ides agg ega e
in o igid amyloid ibe s ha agglu ina e mic obial cells in o clus e s [
89
], hus leading o
he o ma ion o agg ega es ha impai he es ablishmen o new bio ilms. I was p oposed
ha he ca bohyd a es o he mic obial cell wall would be he binding a ge s o AFhPs
a he han he su ace-exposed amyloids. Mo eo e , lipid memb anes may accele a e
AFhP ib illa ion. Howe e , he ole o hese s uc u es in he an i-bio ilm ac i i y o AFhPs
emains o be elucida ed.
Simila ly, an an i-bio ilm ac i i y was iden i ied o he P1 pep ide, a syn he ic pep ide
o 24 amino acids (di e en om he P1 p o ein o S. mu ans), which was designed om he
epea ed mo i s o he Ixodes ick an i eeze glycop o ein (IAFGP) sequence [102]. The P1
pep ide is able o inhibi bio ilm o ma ion o S. mu an s and o he G am-posi i e bac e ia
bu does no possess bac e icidal ac i i y [
103
]. The an i-bio ilm e ec is associa ed wi h
P1 agg ega ion and he o ma ion o an ipa allel
β
-shee s. Howe e , u he expe imen s
a e needed o de e mine whe he he an i-bio ilm e ec is caused by he in e molecula
in e ac ions o P1 agg ega es wi h bac e ial amyloidogenic p o eins [103].
3.2. An i-Amyloid P o eins
The human amyloid p ecu so ans hy e in (TTR) is a 55 kDa homo e ame p o ein
mainly p oduced by he li e . In e es ingly, TTR is s uc u ally simila o he cu li inhibi o
CsgC, and bo h sha e a s able olded
β
-shee - ich s uc u e [
104
,
105
]. TTR is in ol ed in
he anspo o hy oxine (T4) and e inol in plasma and ce eb ospinal luid. Mis olded
p o ein monome s, de i ed om he e ame ic p o ein TTR, can be accumula ed as ib illa
deposi s in di e en o gans and cause he mos common o m o he edi a y ans hy e in
amyloidosis. By compa ison, he homo e ame ic o m o he p o ein has he abili y o
inhibi amyloid o ma ion o amyloidogenic p o eins, such as A
β
, he N- e minal domain
o he bac e ial hyd ogenase HypF and he human isle amyloid polypep ide [
106
–
108
].
Taking in o accoun he an i-amyloid p ope ies o TTR, in a ema kable wo k, Jain e al.
examined he e ec o TTR on CsgA amyloid assembly [
109
]. The incuba ion o CsgA wi h
he e ame p ecu so (W -TTR) e a ded CsgA polyme iza ion, whe eas he incuba ion
wi h he monome ic o m (M-TTR) s ongly p e en ed he o ma ion o CsgA p o o ib illa
and ib illa s uc u es (Figu e 1a). In e es ingly, M-TTR also inhibi ed he assembly o
CsgB in o amyloid agg ega es. The e o e, bo h W -TTR and M-TTR inhibi ed w inkled
pellicle bio ilms o med by E. coli; howe e , he inhibi o y e ec o M-TTR was signi ican ly
mo e po en han ha p oduced by W -TTR. I is possible ha W -TTR equi es e ame
dissocia ion o libe a e he monome s ha a e conside ed he ac i e o ms o ib il inhibi-
ion. Howe e , he use o a highly s able TTR e ame o m (TTR T119M) inhibi ed CsgA
ib illogenesis, indica ing ha he W -TTR e ame dissocia ion was no equi ed o such
inhibi ion [109].
3.3. An ibodies as Na i e-S a e S abilizing Agen s
The adminis a ion o an ibodies o enginee ed a ibodies has been p oposed as one
o he mos p omising he apies o educe amyloid polyme iza ion [
110
]. An ibody-based
immuno he apy has been used o educe he amyloid amoun by s imula ing he clea ance
o he mis olded agg ega es by he immune sys em cells [
111
]. In addi ion, an ibodies
can be used as na i e-s a e s abilizing agen s ha bind o he agg ega ion-p one p o eins,
inc easing hei s abili y and impai ing he agg ega ion endency o human amyloidogenic
p o eins [
112
,
113
]. A ecen pionee ing s udy p oposed he use o an ibodies as na i e-s a e
s abilizing agen s o educe bac e ial amyloid agg ega ion [
90
]. The human monoclonal
An ibio ics 2021,10, 795 16 o 18
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