Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatment

Figures & data

Table 1 Prevalence Of Antimicrobial Resistance Genes In Shigella Spp. Isolated From Different Regions Of The World

Antimicrobial Class	Resistance Mechanism	Genes Mediating Antimicrobial Resistance	Origin	Geographic Origin	Reference
β-Lactams	Class A β-lactamases	blaSHV-2	P	Argentina, France	^Citation32
		blaSHV-11	C, P	India	^Citation191
		blaSHV-12	P	China, Turkey	^Citation40
		blaPER-2	—	Argentina	^Citation32
		blaTEM-1	I, P	Lebanon, Chile, China, India, Iran, US, Djibouti, Denmark, France, Greece, Brazil, South Korea, UK, Romania	^Citation25,Citation26,Citation31,Citation40,Citation120,Citation192
		blaTEM-1b	I, P	China, South Korea	^Citation34,Citation40
		blaTEM-15	–	South Korea	^Citation28
		blaTEM-17		South Korea	^Citation28
		blaTEM-19	–	South Korea	^Citation28
		blaTEM-20	–	South Korea	^Citation28
		blaTEM-52	P	South Korea	^Citation28
		blaCTX-M-1	P	China	^Citation40
		blaCTX-M-2	P	Argentina, Turkey, South Korea, Israel	^Citation30,Citation32,Citation39
		blaCTX-M-3	P	China, Turkey, Argentina, South Korea, India, Israel	^Citation30,Citation39,Citation40
		blaCTX-M-14	P	China, Turkey, Argentina, South Korea, US, Japan	^Citation39,Citation40,Citation193
		blaCTX-M-15	C, P	China, Spain, Iran, South Korea, India, US, Lebanon, Japan, Poland, New Zealand, France, Romania	^Citation26,Citation31,Citation33,Citation34,Citation40,Citation194
		blaCTX-M-22	P	China	^Citation51
		blaCTX-M-24	P	China	^Citation40
		blaCTX-M-27	P	China	^Citation40
		blaCTX-M-28	–	China	^Citation36,Citation51
		blaCTX-M-39	–	Israel	^Citation30
		blaCTX-M-55	P	China, South Korea	^Citation35,Citation40
		blaCTX-M-57	–	China	^Citation51
		blaCTX-M-64	P	Japan	^Citation195
		blaCTX-M-65	P	China	^Citation192
		blaCTX-M-79	P	China	^Citation40
		blaCTX-M-123	P	China	^Citation40
	Class B β-lactamases	blaIMP-like	P	India, France	^Citation43,Citation46
		blaKPC	–	Senegal, France	^Citation46
		blaIMP-3	P	Japan	^Citation44
		blaVIM-like	–	India	^Citation43
	Class C β-lactamases	blaCMY-2	C, P	China, Mexico, India, Iran, Taiwan, Costa Rica, Romania	^Citation48,Citation51
		blaCMY-59	C	Iran	^Citation31
		blaDHA-1	C, I, P	China, India, Israel	^Citation30,Citation51
	Class D β-lactamases	blaoxa-1-like	I, P	Mozambique, Chile, China, India, US, Egypt, Djibouti, Spain, Greece, Denmark, Peru, Iran	^Citation105,Citation193,Citation196
		blaoxa-2-like	I	Mozambique, Spain, Israel	^Citation30,Citation105
		blaoxa-5-like	–	Mozambique, Spain	^Citation105
		blaoxa-30-like	I, P	Senegal, China, France, Japan, Spain, Brazil	^Citation51,Citation91,Citation120
Quinolones	Plasmid-borne resistance	qnrA	P	Iran	^Citation50,Citation75
		qnrB	P	China, India, Iran	^Citation64,Citation65,Citation75
		qnrB4	P	Switzerland	^Citation61
		qnrB19	P	Switzerland	^Citation61
		qnrC	P	India	^Citation65
		qnrS	P	Iran, China, India, Pakistan	^Citation53,Citation66,Citation75,Citation94
		qnrS1	P	Iran, China, Switzerland, US	^Citation48,Citation61,Citation64
		aac-(60)-Ib-cr	P	US, India, Japan, China, Iran	^Citation50,Citation64^–^Citation66
	Efflux pumps	qepA	P	China, Switzerland	^Citation61,Citation64
Fosfomycin	Fosfomycin resistance enzymes	fosA3	P	China	^Citation38
Aminoglycosides: streptomycin		strA	MGE	India, Australia, Chile, Pakistan, South Korea	^Citation86,Citation93,Citation94,Citation97,Citation122
		strB	MGE	India, Chile, Pakistan, South Korea	^Citation86,Citation94,Citation97,Citation122
	Adenyltransferase	aadA1	I, P	Senegal, Bhutan, India, Taiwan, Spain, China, Iran, France, Australia, Brazil, Pakistan, South Korea	^Citation83,Citation86,Citation88,Citation91,Citation94,Citation97,Citation98,Citation120
		aadA2	I, P	Taiwan, Spain, China, South Korea, France, Australia, Korea	^Citation46,Citation83,Citation88,Citation97,Citation98
		aadA5	I, P	Taiwan, China, Iran	^Citation88,Citation98
Tetracycline	Efflux pumps	tetA	C, P	Mozambique, Taiwan, Chile, Peru, Brazil, Iran, Spain, Pakistan, South Korea	^Citation11,Citation88,Citation94,Citation97,Citation104^–^Citation106,Citation120
		tetB	C, P	Mozambique, Taiwan, Peru, France, Brazil, Iran, Spain, Pakistan	^Citation11,Citation46,Citation88,Citation94,Citation104,Citation106,Citation120
		tetG	C, P	Mozambique, Spain	^Citation104,Citation105
Trimethoprim	Dihydrofolate reductases	dfrA1	I, P	Spain, Taiwan, Senegal, Mozambique, India, Bhutan, China, Iran, South Korea, Peru, France, Chile, Australia	^Citation46,Citation83,Citation86,Citation88,Citation91,Citation98,Citation105,Citation122
		dfrA5	I, P	Spain, Senegal, China	^Citation91,Citation98
		dfrA7	I, P	Spain, Iran, France	^Citation46,Citation106
		dfrA8	P	Mozambique, Chile	^Citation105,Citation122
		dfrA12	I, P	Spain, Taiwan, Korea, Australia, South Korea	^Citation11,Citation83,Citation88,Citation97
		dfrA13	P	South Korea	^Citation97
		dfrA14	P	Mozambique, Chile	^Citation105,Citation122
		dfrA14-like	P	Mozambique	^Citation105
		dfrA15	I, P	Spain, Senegal	^Citation91
		dfrA16	P	Spain	^Citation91
		dfrA17	I, P	Taiwan, China, Iran, Brazil	^Citation88,Citation98,Citation106,Citation120
		dfrV	I, P	China, India	^Citation98
Sulfonamides	Plasmid-borne resistance	sul1	I, P	Australia, South Korea, Taiwan	^Citation83,Citation88,Citation97
		Sul2	I, P	Taiwan, India, Peru, Chile, Bangladesh, South Korea	^Citation86,Citation88,Citation97,Citation122,Citation126
		Sul3	I, P	Taiwan	^Citation88
Phenicols	Chloramphenicol acetyltransferase genes	CatA-like	P	Taiwan, Mozambique, India, Peru, France, Brazil, Pakistan	^Citation46,Citation86,Citation88,Citation94,Citation120
		catP	P	Pakistan	^Citation94
	Efflux pumps	cmlA1	I, P	Taiwan, Mozambique	^Citation88,Citation105
Colistin	Plasmid-borne resistance	mcr-1	P	China, Vietnam	^Citation112,Citation116
Macrolide	Enzymatic inactivation	mphA	P	Palestine, Switzerland, Vietnam, China, Canada, UK, Peru	^Citation61,Citation116,Citation127,Citation128,Citation133
	rRNA methylase	ermB	P	Vietnam, Canada, UK	^Citation128,Citation133

Abbreviations: P, plasmid; C, chromosome; I, integron; —, unknown; MGE, mobile genetic element.

Figure 1 Schematic representation of bla_CTX-M-55, bla_CTX-M-15, and bla_TEM-1 genes in different types of plasmid. Arrows indicate positions and directions of different genes and IRL, terminal inverted repeats at the left, IRR, terminal inverted repeats at the right.

Figure 2 Physical map of Shigella atypical class 1 integron and locations of bla_OXA-30 and aadA genes.

Table 2 Frequency Of Amino-Acid And Nucleotide Changes In The Quinolone Resistance–Determining Regions Of ShigellaIsolates In Different Parts Of The World

Target Site Mutations	Codon	Amino-Acid Changes	Nucleotide Mutation	Shigella spp.	Country Of Detection	Reference(s)
gyrA	57	Asn→Lys	AAT→AAA	S. flexneri	China	^Citation197
	69	Gln→Trp	—	S. sonnei	India	^Citation65
	71	Phe→Ser	—	S. sonnei	India	^Citation65
	72	Ser→Pro	—	S. sonnei	India	^Citation65
	75	Met→Leu	—	S. sonnei	India	^Citation65
	80	His→Pro	CAT→CCT	S. flexneri	China	^Citation197
	80	His→ Gly	CAT→GGT	S. dysenteriae	Belgium	^Citation197
	83	Ser→Leu	TCG →TTG	S. sonnei, S. flexneri, S. dysenteriae, S. boydii	China, Bangladesh, Switzerland, Thailand, India	^Citation21,Citation58,Citation61,Citation64
	87	Asp→Asn	GAC→AAC	S. sonnei, S. flexneri, S. dysenteriae	China, Bangladesh, Switzerland, India	^Citation21,Citation52,Citation64
	87	Asp→Gly	GAC→GGC	S. sonnei, S. flexneri, S. dysenteriae	China, Switzerland, Thailand, India	^Citation21,Citation61,Citation64
	87	Asp→Tyr	GAC→TAC	S. sonnei, S. flexneri	Switzerland	^Citation61
	90	Ser→Cys	—	S. sonnei	India	^Citation65
	94	Met→Leu	—	S. sonnei	India	^Citation65
	106	His→Pro	—	S. sonnei	India	^Citation65
	161	Asn→His	—	S. sonnei	India	^Citation65
	163	Thr→Ala	—	S. sonnei	India	^Citation65
	196	Val→Ala	—	S. flexneri, S. dysenteriae	India	^Citation21
	211	His→Tyr	CAC→TAC	S. sonnei, S. flexneri	China, Bangladesh	^Citation8,Citation62,Citation64
gyrB	517	Gln→Arg	CAG→CGA	S. flexneri	China	^Citation62,Citation71
parC	64	Ala→Asp	GCC→GAC	S. sonnei, S. flexneri,	India, China	^Citation65
	64	Ala→Cys	GCC→TGC	S. sonnei	China	^Citation65
	80	Ser→Ile	AGC→ATC	S. sonnei, S. flexneri, S. dysenteriae,	China, Bangladesh, Switzerland, India	^Citation21,Citation40,Citation57,Citation61,Citation62,Citation64
	81	Ala→Pho	—	S. flexneri	China	^Citation71
	83	Ser→Leu	—	S. flexneri	China	^Citation30
	85	Ala→Thr	GCG→ACG	S. flexneri	China	^Citation71
	85	Ala→Ser	GCG→TCG	S. boydii	Switzerland	^Citation61
	86	Met→Trp	ATG→TGG	S. sonnei	China	^Citation64
	91	Gln→His	—	S. flexneri	China	^Citation71
	93	Phe→Val	—	S. flexneri, S. dysenteriae	India	^Citation21
	101	Asp→Glu	—	S. flexneri, S. dysenteriae,	India	^Citation21
	110	Asp→Glu	—	S. flexneri, S. dysenteriae	India	^Citation21
	111	Asp→His	GAT→CAT	S. flexneri	China	^Citation62,Citation64
	129	Ser→Pro	TCC→CCC	S. sonnei	China	^Citation62,Citation64
parE	408	Gly→Asp	GGC→GAC	S. flexneri	China	^Citation62
	458	Ser→Leu	TCG→TTG	S. sonnei, S. flexneri, S. dysenteriae	China, India	^Citation62
	458	Ser→Ala	TCG→GCG	S. sonnei, S. flexneri, S. dysenteriae	India	^Citation62

Note: —, unknown.

Figure 3 Structure of genes surrounding mcr-1 in S. flexneri.

Figure 4 Variable regions of class 1 (A) and class 2 (B) integrons reported in different geographic area. Horizontal arrows indicate transcriptional orientation of genes.

Table 3 Overview Of Shigella Vaccines In A Aifferent Phase

Class/type	Investigational Vaccines	Delivery Systems	Target Antigen (Type)	Valued Immunoresponse	Status And Results	Limitations	Development Phase	Reference
Live vaccine
Live-vaccine candidate strain	Escherichia albertii strain DM104	Intranasal	Whole-cell E. albertii	Humoral	Completed, efficacy, protection in guinea pigs	Unknown	Preclinical	^Citation198
Attenuated vaccines
Live attenuated strains	S. flexneri 2a WRSf2G12, WRSf2G15	Ocular	virG, set, senA, sbB2 genes	Humoral	Ongoing, protection in guinea pigs	Needs balancing immunogenicity with reactogenicity	Preclinical	^Citation176
	S. dysenteriae type 1 WRSd1	Oral	virG gene	Humoral	Efficacy when given orally	Transient diarrhea	Phase I	^Citation199
	S. flexneri 2a (SC602)	oral	virG, iuc genes	Humoral	Completed, efficacy, protection	ND	Phas IIB	^Citation200
	S. dysenteriae type 1 SC599	Oral	virG, ent, fep, stxA genes	Humoral	Completed, efficacy, protection	Unknown	Phase II	^Citation201
	S. sonnei WRSS1	Oral	virG gene	Humoral	Phase I, ongoing, protection in adults	Children elicited lower mucosal immunoresponses than adults	Phase I	^Citation177
	S. sonnei WRSs2, WRSs3	Oral	virG, senA, senB, msbB2 genes	Humoral	Ongoing, need for human challenge models for the efficacy of the vaccine	Fever, transient diarrhea	Phase I	^Citation176
	Trivalent of S. flexneri serotypes	Intranasal	guaBA gene	Humoral	Ongoing, prevention in guinea pigs and needs further development	Unknown	Preclinical	^Citation179
	S. flexneri 2a CVD 1208S	Oral	guaBA, set, sen genes	Humoral and cellular	Completed, efficacy, prevention and induces diverse T-CMI responses in human volunteers	ND	Phase II	^Citation180
	RNA-binding protein mutants of S. dysenteriae type 1 and S. sonnei	Ocular and oral	hfq gene and ipaBCDA plasmid	Humoral	Ongoing, induced protective immunity	Animals vaccinated in the eye showed fewer symptoms	Preclinical	^Citation181
Hybrid and live attenuated vectors	Salmonella enterica serovar Typhi strain, Ty21a	Oral	O-antigen biosynthesis gene	Humoral	Completed, efficacy, protection in mice	Unknown	Preclinical	^Citation182
	S. flexneri 2a	Intranasal and oral	virG, aroA genes	Humoral	Ongoing, efficacy and future investigation need for more attenuated recombinant mutant strains	Fever and diarrhea	Phase II	^Citation202
	Live transconjugant Shigella hybrid (LTSHΔstx) strain	Oral	stx gene	Humoral and cellular	Completed, efficacy and good protection in mice	Unknown	Preclinical	^Citation203
	Escherichia coli K12	Oral	pWR110–R64drdll invasiveness plasmid	Humoral	Stopped, causes mild diarrhea in human primates	Fever, mild diarrhea to frank dysentery	Preclinical	^Citation204
	E. coli K12, EcSf2a-3, EcSf2a-5	Oral	virG, aroD genes	Humoral	Stopped, EcSf2a was immunogenic but also reactogenic and thus not sufficiently attenuated in the guinea pig	Not sufficiently attenuated	Preclinical	^Citation204
Inactivated vaccines
Whole cell–killed vaccines	Shigella with a truncated O-SP	Intranasal	wzy gene	Humoral	Completed, efficacy, protection	ND	Preclinical	^Citation205
	S. flexneri 2a	Oral	Inactivated whole cells	Humoral and cellular	Completed, safety, robust immunoresponse	ND	Phase I	^Citation206
	S. sonnei	Oral	Inactivated whole cells	Humoral	Completed, efficacy, protection	ND	Phase I	^Citation205
	Trivalent of Shigella whole cells	Intranasal	Formalin inactivation of S. flexneri 2a, S. sonnei, and S. flexneri 3a	Humoral	Completed, efficacy, protection from lethality in guinea pig infection model	Unknown	Preclinical	^Citation184
	Heat-killed multiple serogroups/serotypes of Shigella (HKMS)	Oral	S. dysenteriae 1, S. flexneri 2a, S. flexneri 3a, S. flexneri 6, S. boydii 4 and S. sonnei	Humoral and cellular	Completed, efficacy, protection in rabbit infection model	ND	Preclinical	^Citation185
Subunit vaccines	IpaDB fusion proteins	Intradermal	Invasion plasmid antigens B and D (IpaB and IpaD)	Humoral	Ongoing, protective efficacy using a mouse pulmonary infection model	ND	Preclinical	^Citation178
	rIpaB domain rGroEL	Lung	S. flexneri IpaB, S. Typhi GroEL	Humoral	Immunogenic and protective efficacy against S. flexneri, S. boydii and S. sonnei in BALB/c mouse infection model	ND	Preclinical	^Citation207
Glycoconjugate candidates	Bioglycoconjugates	Intramuscular	S. dysenteriae 1 LPS exoprotein A	Humoral	Ongoing, protection, additional serotypes will be tested shortly	ND	Phase I	^Citation208
	Lipid-linked S. dysenteriae–type 1 O-polysaccharide	Intramuscular	O-SP Ag	Humoral	Ongoing, need future studies using synthetic saccharides of different size	Low level of antibodies	Preclinical	^Citation209
	O-polysaccharide covalently linked to immunogenic carrier proteins	Subcutaneous	O-SP Ag	Humoral	Ongoing studies	Unknown	Preclinical	^Citation174
	Synthetic oligosaccharides	Intramuscular	S. flexneri 2a O-SP Ag tetanus toxoid	Humoral	Ongoing, need future studies for the development of multivalent glycoconjugate vaccines	Unknown	Preclinical	^Citation209
Novel antigen candidates	Artificial Invaplex (recombinant IpaB and IpaC proteins with purified Shigella LPS)	Intranasal	LPS, IpaB, and IpaC Ag	Humoral	Efficacy, protection in mice, need future testes for determination of safety and immune response in humans	ND	Preclinical	^Citation186
	Triacylated S-LPS	Parenteral	Partial alkaline deacylation of S-LPS	Humoral	Completed, efficacy, protection with robust humoral immunoresponse	Unknown	Phase I	^Citation108
	GMMA protein particles	-	Outer-membrane particles from S. sonnei and S. flexneri 2a	Humoral	Completed, good safety and immunogenicity profiles in healthy adults	ND	Phase IIa	^Citation187
	ΔtolA-OMV vaccine	Intramuscular	Outer-membrane vesicles, disruption of tolA gene from S. boydii 4	Humoral	An ongoing, potentially cost-effective vaccine in the mouse infection model	ND	Preclinical	^Citation210
	OMV-nanoparticle vaccine	Intranasal	Shigella outer-membrane vesicles	Humoral	Ongoing, need future studies for the development of a multivalent vaccine	ND	Preclinical	^Citation188
Recombinant probiotic–based candidates	Lactococcus lactis bacterium like particles	Intranasal	IpaB and IpaD	Humoral	Ongoing, prevention in adult and infant mice	Unknown	Preclinical	^Citation183
	L. lactis	Subcutaneous	ompA of S. dystenteriae type 1	Humoral	Ongoing, efficacy of provoked immunoresponses in affording protection from Shigella needs to be evaluated	Unknown	Preclinical	^Citation183

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