Table 2.
The information of antivirulence drug candidates discussed in this review.
| Targets | Names | Types | Tested Strains9 | Status | Refs |
|---|---|---|---|---|---|
| T3SS | |||||
| PcrV & PsI1 | MEDI3902 (BiS4αPa) | Antibodies (Modified bispecific) | PAO1 (S), 6206 (NA), 6077 (R) | Phase 1 and 2 (NCT02255760, NCT02696902) completed with no ideal results |
(DiGiandomenico et al., 2014) |
| PcrV | KB001-A | Antibodies (PEGylated-Fab) | PA103 (R) | Phase 1 and 2 (NCT00638365, NCT00691587, NCT01695343) completed with no ideal results |
(Baer et al., 2009) |
| ?2 | Fluorothiazinon (FT) | Small molecules (Chemicals) | PAO1 (S), PA103 (R), other clinical isolates (S, R) | Phase 2 (NCT03638830) Recruiting |
(Sheremet et al., 2018) |
| PscN & flagella3 | INP1855 | Small molecules (Chemicals) | PA103 (R), CHA (NA) | Preclinical (verified by a mouse model) |
(Anantharajah et al., 2016) |
| PscF-PscE-PscG complex4 | dHTSN and dHTSN1 | Small molecules (Natural herbal compounds) | PAO1 (S) | Preclinical (verified by a mouse model) |
(Feng et al., 2019) |
| Quorum-sensing (QS) & Biofilm | |||||
| PqsR3 | M64 | Small molecules (Chemicals) | PA14 (R), other clinical isolates (R) | Preclinical (verified by two mouse models) |
(Starkey et al., 2014) |
| PqsR3 | Clofoctol | Small molecules (FDA-approved drugs) | PAO1 (S), PA14 (R), other clinical isolates (S, R) | Preclinical (verified by a Galleria mellonella larvae model) |
(D'Angelo et al., 2018) |
| LasR5 | Furanone C30 | Small molecules (Natural food compounds) | PAO1 (S) | Preclinical (verified by a mouse model) |
(Hentzer et al., 2003; Wu et al., 2004) |
| LasR3 | MHY1383 and MHY1387 | Small molecules (Chemicals) | PAO1 (S) | Preclinical (verified by a Tenebrio molitor larvae model) |
(Hwang et al., 2021) |
| RhlR and LasR | Meta-bromo-thiolactone (mBTL) | Small molecules (Chemicals) | PA14 (R) | Preclinical (verified by a Caenorhabditis elegans model) |
(O’Loughlin et al., 2013) |
| c-di-GMP6 | Nitric oxide (NO) | Small molecules (Chemicals) | PAO1 (S) | Phase 2 (NCT02295566) completed, data not shown |
(Barraud et al., 2006) |
| DNA-Ca2+-DNA bridges and biofilm EPS matrix | OligoG CF-5/2010 | Alginate oligomer (Natural food compounds) | PAO1 (S), NH57388A (NA) | Phase 1 and 2 (NCT01465529, NCT01991028, NCT00970346, NCT02157922, NCT02453789) completed, data not shown |
(Hengzhuang et al., 2016) |
| ?2,7 | AR-501 (inhaled gallium citrate) | Small molecules (Chemicals) | NA | Phase 1 and 2 (NCT03669614) Recruiting |
(Woo et al., 2019) |
| Siderophores | |||||
| Pyoverdine | LK11, LK31, and LK31a | Small molecules (Chemicals) | PAO1 (S), PA14 (R), Boston 41501 (NA), KM 306 (NA), 6092 (NA), WCS365 (NA) | Preclinical (verified by a Caenorhabditis elegans model) |
(Kirienko et al., 2018) |
| Proteases | |||||
| LasB | Mercaptoacetamide 2 | Small molecules (Chemicals) | PA14 (R) | Preclinical (verified by a Galleria mellonella larvae model) |
(Kany et al., 2018) |
| LasB | Mercaptoacetamide derivative 7g and 4 | Small molecules (Chemicals) | PA14 (R) | Preclinical (verified by a Galleria mellonella larvae model) |
(Kaya et al., 2022) |
| LasB | phendione, Ag-phendione and Cu-phendione | Small molecules (Chemicals) | Boston 41501 (NA), 09HC (R) | Preclinical (verified by a Galleria mellonella larvae model) |
(Galdino et al., 2019) |
| Exopolysaccharides | |||||
| Alginate | AR-105 (Aerucin®) | Antibodies | NA | Phase 2 (NCT03027609) completed with no ideal results |
(Loos et al., 2019) |
| Alginate (by targeting Alg44)8 | Ebselen and its analogues | Small molecules (Chemicals) | PA14 (R) | Preclinical | (Kim et al., 2021) |
| Outer membrane components | |||||
| O-polysaccharide moiety in LPS | KBPA-101 | Antibodies | FT-2 (NA), 2310.55 (NA), ATCC 33348 (NA), other clinical isolates (NA) | Phase 1 and 2 (NCT00851435) completed, data not shown |
(Lazar et al., 2009; Horn et al., 2010; Secher et al., 2011) |
| Surface appendages | |||||
| Flagelin | Chicken IgY | Antibodies | PAO1 (S), HABS1 (NA), PA-NED995 (NA), PA-NED1033 (NA) | Phase 1, 2 and 3 (NCT00633191, NCT01455675) completed, data not shown |
(Nilsson et al., 2007) |
| Bacterial metabolism | |||||
| Glycine metabolism | Cysteamine | Small molecules (FDA-approved drugs) | PAO1 (S), PA14 (R), NH57388A (NA), NH57388B (NA) | Preclinical (verified by a Galleria mellonella larvae model) |
(Fraser-Pitt et al., 2021) |
| Polyphosphate kinase 1 and 2 (PPK1, PPK2) enzymes | Gallein | Small molecules (Chemicals) | PAO1 (S) | Preclinical (verified by a Caenorhabditis elegans model) |
(Rashid et al., 2000; Neville et al., 2021) |
1PsI is an exopolysaccharide involved P. aeruginosa biofilm formation.
2The specific target remains unclear.
3The detailed mechanism requires further confirmation.
4dHTSN and dHTSN1 are competitive inhibitors of PscF binding to PscE-PscG.
5Off-target effects may occur; resistant strains have been discovered.
6c-di-GMP is a key regulator of P. aeruginosa biofilm formation and dispersal.
7AR-501 acts as iron analog to starve bacteria of iron.
8Ebselen and its analogues covalently modify Alg44, interrupt its binding to c-di-GMP, and subsequently inhibit alginate secretion.
9The P. aeruginosa strains that are derived from standard strains by gene mutations are not included. R, resistant to one or more antibiotics; S, susceptible to all antibiotics; NA, the information is not available.