Edited by: Ghassan M. Matar, American University of Beirut, Lebanon
Reviewed by: Sang Sun Yoon, Yonsei University, South Korea; Ravi Jhaveri, University of North Carolina Hospitals, USA
*Correspondence: Sang Hee Lee
†These authors have contributed equally to this work.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Among
Many reports have shown that
Although recent genomic and phenotypic analyses of
Porin (OmpA, Omp33-36, Omp22, CarO, OprD-like) | Adherence and invasion, induction of apoptosis, serum resistance, biofilm formation, persistence | Choi et al., |
Capsular polysaccharide | Growth in serum, survival in tissue infection, biofilm formation | Russo et al., |
Lipopolysaccharide (LPS) | Serum resistance, survival in tissue infection, evasion of the host immune response | Luke et al., |
Phospholipase (PLC and PLD) | Serum resistance, invasion, |
Camarena et al., |
Outer membrane vesicle (OMV) | Delivery of virulence factors, horizontal transfer of antibiotic resistance gene | Kwon et al., |
Iron acquisition system (acinetobactin and NfuA) | Gaddy et al., |
|
Zinc acquisition system (ZnuABC and ZigA) | Hood et al., |
|
Manganese acquisition system (MumC and MumT) | Juttukonda et al., |
|
Type II protein secretion system | Johnson et al., |
|
Type VI protein secretion system | Killing of competing bacteria, host colonization | Carruthers et al., |
Type V protein secretion system | Biofilm formation, adherence | Bentancor et al., |
Penicillin-binding protein 7/8 and β-lactamase PER-1 | Serum resistance, |
Sechi et al., |
CipA | Serum resistance, invasion | Koenigs et al., |
Tuf | Serum resistance | Koenigs et al., |
RecA | Aranda et al., |
|
SurA1 | Serum resistance, |
Liu D. et al., |
GigABCD | Gebhardt et al., |
|
UspA | Elhosseiny et al., |
|
GacS and PaaE | Neutrophil influx | Cerqueira et al., |
Pili | Adherence, biofilm formation | Tomaras et al., |
OmpR/EnvZ | Killing of host cells | Tipton and Rather, |
FhaBC | Adherence, killing of host cells | Perez et al., |
AbeD | Killing of host cells | Srinivasan et al., |
Porins are outer membrane proteins associated with modulating cellular permeability. OmpA is a β-barrel porin and one of the most abundant porins in the outer membrane. In
Furthermore, OmpA is also involved in antimicrobial resistance of
The 33- to 36-kDa Omp protein (Omp33-36), which acts as a water passage channel, is another outer membrane porin associated with
Omp22 has also been identified as a novel, conserved, and safe antigen for developing effective vaccines to control
Beyond OmpA, the
One study showed that capsular polysaccharides are involved in antimicrobial resistance of
LPS is the major component of the outer leaflet of the outer membrane in most Gram-negative bacteria and is an immunoreactive molecule that induces release of tumor necrosis factor and interleukin 8 from macrophages in a Toll-like receptor 4 (TLR4)-dependent manner (Erridge et al.,
Phospholipase is a lipolytic enzyme essential for phospholipid metabolism and is a virulence factor in many bacteria, such as
OMVs are spherical, 20–200 nm diameter vesicles secreted by the outer membranes of various Gram-negative pathogenic bacteria (Kulp and Kuehn,
Due to the importance of OMVs in
Although iron is one of the most abundant elements in environmental and biological systems, ferric iron is relatively unavailable to bacteria in the preferred state, because of its poor solubility (10−17 M solubility limit for ferric iron) under aerobic and neutral pH conditions as well as due to chelation by low-molecular-weight compounds, such as heme, or high-affinity iron-binding compounds, such as lactoferrin and transferrin (Rakin et al.,
The
The innate immune metal-chelating protein calprotectin inhibits bacterial growth by host-mediated chelation of metals, such as zinc (Zn2+ and Zn) and manganese (Mn2+ and Mn) (Corbin et al.,
The mechanism employed by
Several protein secretion systems have been identified in
The presence of T6SS in
The type V system autotransporter Ata has also been characterized in
Although PBPs are commonly involved in resistance to β-lactam antibiotics, PBP7/8 encoded by the
Interestingly, β-lactamase PER-1 has been suggested to be an
A growth analysis of 250,000
Biofilm formation plays an important role in immune evasion by
Other virulence-related proteins have been identified, including OmpR/EnvZ (Tipton and Rather,
β-Lactamases | Class A | TEM-1 | Chen et al., |
TEM-92 | Endimiani et al., |
||
GES-1 | Al-Agamy et al., |
||
GES-5 | Al-Agamy et al., |
||
GES-11 | Moubareck et al., |
||
GES-12 | Bogaerts et al., |
||
GES-14 | Bogaerts et al., |
||
PER-1 | Jeong et al., |
||
PER-2 | Pasteran et al., |
||
PER-7 | Bonnin et al., |
||
CTX-M-2 | Nagano et al., |
||
CTX-M-15 | Potron et al., |
||
SCO-1 | Poirel et al., |
||
VEB-1 | Fournier et al., |
||
KPC-2 | Martinez et al., |
||
KPC-10 | Robledo et al., |
||
CARB-4 | Ramirez et al., |
||
CARB-10 | Potron et al., |
||
Class B | IMP-1 | Tognim et al., |
|
IMP-2 | Riccio et al., |
||
IMP-4 | Chu et al., |
||
IMP-5 | Koh et al., |
||
IMP-6 | Gales et al., |
||
IMP-8 | Lee M. F. et al., |
||
IMP-11 | Yamamoto et al., |
||
IMP-19 | Yamamoto et al., |
||
IMP-24 | Lee M. F. et al., |
||
VIM-1 | Tsakris et al., |
||
VIM-2 | Yum et al., |
||
VIM-3 | Lee M. F. et al., |
||
VIM-4 | Tsakris et al., |
||
VIM-11 | Lee M. F. et al., |
||
NDM-1 | Chen et al., |
||
NDM-2 | Espinal et al., |
||
NDM-3 | Kumar, |
||
SIM-1 | Lee et al., |
||
Class C | AmpC | Bou and Martinez-Beltran, |
|
Class D | |||
OXA-2 subgroup | OXA-21 | Vila et al., |
|
OXA-10 subgroup | OXA-128 | Giannouli et al., |
|
OXA-20 subgroup | OXA-37 | Navia et al., |
|
OXA-23 subgroup | OXA-23 | Heritier et al., |
|
OXA-133 | Mendes et al., |
||
OXA-239 | Gonzalez-Villoria et al., |
||
OXA-24 subgroup | OXA-24 | Bou et al., |
|
OXA-25, OXA-26, OXA-27 | Afzal-Shah et al., |
||
OXA-40 | Heritier et al., |
||
OXA-72 | Wang et al., |
||
OXA-143 | Higgins et al., |
||
OXA-182 | Kim et al., |
||
OXA-51 subgroup | OXA-51 | Brown et al., |
|
OXA-64, OXA-65, OXA-66, OXA-68, OXA-70, OXA-71 | Hamouda et al., |
||
OXA-69, OXA-75, OXA-76, OXA-77 | Heritier et al., |
||
OXA-79, OXA-80, OXA-104, OXA-106~ OXA-112 | Evans et al., |
||
OXA-82, OXA-83, OXA-83, OXA-84 | Turton et al., |
||
OXA-86, OXA-87 | Vahaboglu et al., |
||
OXA-88, OXA-91, OXA-93, OXA-94, OXA-95, OXA-96 | Koh et al., |
||
OXA-92 | Tsakris et al., |
||
OXA-113 | Naas et al., |
||
OXA-58 subgroup | OXA-58 | Dijkshoorn et al., |
|
OXA-96 | Koh et al., |
||
OXA-97 | Poirel et al., |
||
OXA-143 subgroup | OXA-253 | de Sa Cavalcanti et al., |
|
OXA-235 subgroup | OXA-235 | Higgins et al., |
|
Efflux pumps | Resistance-nodulation-division superfamily | AdeABC | Magnet et al., |
AdeFGH | Coyne et al., |
||
AdeIJK | Damier-Piolle et al., |
||
Major facilitator superfamily | TetA | Ribera et al., |
|
TetB | Vilacoba et al., |
||
CmlA | Coyne et al., |
||
CraA | Roca et al., |
||
AmvA | Rajamohan et al., |
||
AbaF | Sharma et al., |
||
Multidrug and toxic compound extrusion family | AbeM | Su et al., |
|
Small multidrug resistance family | AbeS | Srinivasan et al., |
|
Other efflux pumps | EmrAB-TolC | Nowak-Zaleska et al., |
|
A1S_1535, A1S_2795, and ABAYE_0913 | Li L. et al., |
||
Permeability defects | Porin | OmpA | Smani et al., |
CarO | Mussi et al., |
||
Omp22-33 | Bou et al., |
||
Omp33-36 | del Mar Tomas et al., |
||
Omp37 | Quale et al., |
||
Omp43 | Dupont et al., |
||
Omp44 | Quale et al., |
||
Omp47 | Quale et al., |
||
Aminoglycoside-modifying enzymes | Aminoglycoside acetyltransferases | AAC3 ( |
Nemec et al., |
AAC(6′) ( |
Doi et al., |
||
Aminoglycoside adenyltransferases | ANT(2″) ( |
Nemec et al., |
|
ANT(3″) ( |
Cho et al., |
||
Aminoglycoside phosphotransferases | APH(3′) ( |
Gallego and Towner, |
|
APH(3″) | Cho et al., |
||
Alteration of target sites | Change of penicillin binding protein(PBP) | PBP2 | Gehrlein et al., |
16S rRNA methylation | ArmA | Yu et al., |
|
Ribosomal protection | TetM | Ribera et al., |
|
DNA gyrase | GyrA/ParC | Higgins et al., |
|
Dihydrofolate reductase | DHFR | Mak et al., |
|
FolA | Mak et al., |
||
Lipopolysaccharide | PmrC, LpxA, LpxC, LpxD | Adams et al., |
|
Other mechanisms | S-adenosyl-L-methionine-dependent methyltransferase | Trm | Chen et al., |
1-Acyl-sn-3-phosphate acyltransferase | PlsC | Li X. et al., |
|
Peptidase C13 family | Abrp | Li X. et al., |
|
Cell division proteins | BlhA, ZipA, ZapA, and FtsK | Knight et al., |
|
SOS response | RecA | Aranda et al., |
Inactivation of β-lactams by β-lactamases is a major antibiotic resistance mechanism in
Class A β-lactamases inhibited by clavulanate hydrolyze penicillins and cephalosporins more efficiently than carbapenems, except for some KPC type enzymes (Jeon et al.,
Unlike the serine-dependent β-lactamases (classes A, C, and D), class B β-lactamases are metallo-β-lactamases (MBLs) that require zinc or another heavy metal for catalysis (Jeon et al.,
Class C β-lactamases pose therapeutic problems because they can confer resistance to cephamycins (cefoxitin and cefotetan), penicillins, cephalosporins, and β-lactamase inhibitor combinations, but are not significantly inhibited by clinically used β-lactamase inhibitors, such as clavulanic acid (Jeon et al.,
Class D β-lactamases are called OXAs (oxacillinases), because they commonly hydrolyze isoxazolylpenicillin oxacillin much faster than benzylpenicillin (Jeon et al.,
Efflux pumps are associated with resistance against many different classes of antibiotics, such as imipenem (Hu et al.,
AdeABC in the resistance-nodulation-division superfamily is associated with aminoglycoside resistance (Magnet et al.,
CmlA and CraA are major facilitator superfamily efflux pumps related with chloramphenicol (Fournier et al.,
AbeM is in the multidrug and toxic compound extrusion family and confers resistance to imipenem and fluoroquinolones (Su et al.,
Some other efflux pumps, such as MacAB-TolC (Kobayashi et al.,
A change in envelope permeability can influence antibiotic resistance. For example, porins form channels that allow transport of molecules across the outer membrane and play a significant role in
Besides outer membrane proteins, envelope components, such as LPS and peptidoglycans, also affects antibiotic resistance of
Aminoglycoside-modifying enzymes are the major mechanism by which
Modifications in antibiotic target sites for antibiotics can induce antibiotic resistance in
AdeABC is associated with decreased susceptibility to tigecycline (Ruzin et al.,
The
Increased expression of mutagenesis-related genes, such as the SOS response genes, is a well-understood mechanism of
Although carbapenems are effective antibiotics to treat
Carbapenem +ampicillin+sulbactam+ | Carbapenem-resistant | Combination therapy with ampicillin-sulbactam and meropenem is effective against skin and soft tissue infection | Hiraki et al., |
|
Multidrug-resistant | The combination of a carbapenem and ampicillin/sulbactam was associated with a better outcome than the combination of a carbapenem and amikacin, or a carbapenem alone | Kuo et al., |
||
Carbapenem +minocycline | Multidrug-resistant | Minocycline in combination with rifampicin, imipenem, and colistin showed bactericidal synergy in most of the isolates which did not harbor the |
Rodriguez et al., |
|
Carbapenem +tigecycline+colistin | Case report | Multidrug-resistant, colistin-susceptible | A patient with bacteremia had a favorable clinical outcome by a meropenem/colistin/tigecycline combination therapy | Candel et al., |
Carbapenem +colistin | Extensively drug-resistant, colistin-susceptible | Effective; 80% of patients were treated successfully | Ozbek and Senturk, |
|
Multidrug-resistant, colistin-susceptible | Imipenem/colistin showed best synergy effects | Pongpech et al., |
||
Multidrug-resistant, colistin-susceptible | Meropenem/colistin can inhibit bacterial regrowth at 24 h | Lee C. H. et al., |
||
Colistin-susceptible and colistin-resistant | Subinhibitory meropenem/colistin showed synergy against 49 of 52 strains at 24 h | Pankuch et al., |
||
Extensively drug-resistant, colistin-susceptible | Combinations of colistin/rifampicin, colistin/meropenem, colistin/minocycline and minocycline/meropenem are synergistic | Liang et al., |
||
A retrospective study | Extensively drug-resistant, colistin-susceptible | Colistin/carbapenem and colistin/sulbactam resulted in significantly higher microbiological eradication rates, relatively higher cure and 14-day survival rates, and lower in-hospital mortality compared to colistin monotherapy in patients with bloodstream infections | Batirel et al., |
|
Carbapenem-resistant, colistin-susceptible | Synergistic effects against all 12 isolates | Liu X. et al., |
||
Extensively drug-resistant, colistin-susceptible and colistin-resistant | Colistin/fusidic acid and colistin/rifampicin were synergistic in a murine thigh-infection model; The colistin-meropenem combination was also effective when the colistin MIC is ≤32 mg/L. | Fan et al., |
||
Extensively drug-resistant | The daptomycin-colistin combination was the most effective; the colistin/imipenem combination was also effective | Cordoba et al., |
||
Carbapenem +colistin+rifampicin | Case report | Multidrug-resistant, colistin-susceptible | Successful treatment by a meropenem/colistin/rifampicin combination therapy in a case of multifocal infection | Biancofiore et al., |
Carbapenem+plazomicin | Carbapenem-resistant | Synergistic activity | Garcia-Salguero et al., |
|
Imipenem+polymyxin B | Carbapenem-resistant | Doripenem, meropenem, or imipenem displayed similar pharmacodynamics in combination with polymyxin B | Lenhard et al., |
|
Meropenem+ polymyxin B | Multidrug-resistant | Combinations of polymyxin B/meropenem and polymyxin B/meropenem/fosfomycin showed high synergistic activity | Menegucci et al., |
|
Carbapenem-resistant | Intensified meropenem dosing in combination with polymyxin B synergistically killed carbapenem-resistant strains, irrespective of the meropenem MIC | Lenhard et al., |
||
Carbapenem-resistant | Doripenem, meropenem, or imipenem displayed similar pharmacodynamics in combination with polymyxin B | Lenhard et al., |
||
Doripenem+tigecycline | Multidrug-resistant, doripenem-resistant | Synergistic activity | Principe et al., |
|
Doripenem+colistin | Multidrug-resistant, doripenem-resistant | Synergistic activity | Principe et al., |
|
Doripenem+polymyxin B | Carbapenem-resistant | Doripenem, meropenem, or imipenem displayed similar pharmacodynamics in combination with polymyxin B | Lenhard et al., |
|
Polymyxin-heteroresistant | The polymyxin B/doripenem combination resulted in rapid and extensive initial killing within 24 h, which was sustained over 10 days | Rao et al., |
||
Doripenem+amikacin | Multidrug-resistant, doripenem-resistant | Synergistic activity | Principe et al., |
|
Ampicillin+sulbactam | Multi-drug resistant | Ampicillin/sulbactam therapy significantly decreased the risk of death in patients with bloodstream infections | Smolyakov et al., |
|
Sulbactam+colistin | A retrospective study | Extensively drug-resistant, colistin-susceptible | Colistin/carbapenem and colistin/sulbactam resulted in significantly higher microbiological eradication rates, relatively higher cure and 14-day survival rates, and lower in-hospital mortality compared to colistin monotherapy in patients with bloodstream infections | Batirel et al., |
A retrospective study | Multidrug-resistant | The colistin/sulbactam combination therapy is promising in patients with ventilator-associated pneumonia | Kalin et al., |
|
Tazobactam+colistin | Colistin-susceptible | Tazobactam plus colistin showed synergy | Sakoulas et al., |
|
Minocycline+colistin | Extensively drug-resistant | Combinations of colistin/rifampicin, colistin/meropenem, colistin/minocycline and minocycline/meropenem are synergistic | Liang et al., |
|
Minocycline-resistant | Minocycline/colistin synergistically killed minocycline-resistant isolates; minocycline/colistin also significantly improved the survival of mice and reduced the number of bacteria present in the lungs of mice | Yang et al., |
||
Multidrug-resistant | Minocycline in combination with rifampicin, imipenem, and colistin showed bactericidal synergy in most of the isolates which did not harbor the |
Rodriguez et al., |
||
Minocycline+rifampicin | Multidrug-resistant | Synergistic effect of minocycline/rifampicin and minocycline/amikacin combinations in a mouse lung infection model | He S. et al., |
|
Multidrug-resistant | Minocycline in combination with rifampicin, imipenem, and colistin showed bactericidal synergy in most of the isolates which did not harbor the |
Rodriguez et al., |
||
Minocycline+amikacin | Multidrug-resistant | Synergistic effect of minocycline/rifampicin and minocycline/amikacin combinations in a mouse lung infection model | He S. et al., |
|
Tigecycline+colistin | Carbapenem-resistant, colistin-susceptible | Good synergy | Ozbek and Senturk, |
|
Extensively drug-resistant, colistin-susceptible | Good synergy | Dizbay et al., |
||
Tigecycline-non-susceptible | Good synergy | Principe et al., |
||
Carbapenem-resistant, colistin-susceptible and colistin-resistant | Good synergy | Peck et al., |
||
Extensively drug-resistant | Mutlu Yilmaz et al., |
|||
Tigecycline+polymyxin B | Carbapenem-resistant, polymyxin-heteroresistant | Combination of polymyxin B-with higher tigecycline concentrations result in sustained bactericidal activity | Rao et al., |
|
Carbapenem-resistant | Synergistic effects in combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose | Hagihara et al., |
||
Tigecycline+amikacin | Multidrug-resistant | Synergistic bactericidal activities | Moland et al., |
|
Colistin+rifampicin | Multidrug-resistant, colistin-susceptible | Efficacy |
Pachon-Ibanez et al., |
|
Case report | Carbapenem-resistant, colistin-susceptible | Efficacy in 7 of 10 patients with ventilator-associated pneumonia | Song et al., |
|
Case report | Multidrug-resistant, colistin-susceptible | Efficacy in 22 of 29 critically ill patients with pneumonia and bacteremia | Bassetti et al., |
|
Multidrug-resistant, colistin-susceptible | Synergistic effect in prolonging survival | Pantopoulou et al., |
||
Clinical trial | Multidrug-resistant, colistin-susceptible | Favorable for all 26 nosocomial infection patients | Motaouakkil et al., |
|
Carbapenem-resistant, colistin-susceptible | Effective for strains highly resistant to imipenem and moderately resistant to rifampicin | Montero et al., |
||
Multidrug-resistant, colistin-susceptible | Synergistic effect against 11 of 13 isolates | Hogg et al., |
||
Extensively drug-resistant | Combinations of colistin/rifampicin, colistin/meropenem, colistin/minocycline and minocycline/meropenem are synergistic | Liang et al., |
||
Multidrug-resistant, colistin-susceptible | Colistin/rifampicin was fully synergistic against 4 of 5 isolates; colistin/meropenem and colistin/azithromycin were synergistic against 3 of 5 isolates; colistin/doxycycline was partially synergistic or additive against 5 isolates | Timurkaynak et al., |
||
Case report | Carbapenem-resistant, colistin-susceptible | Rifampicin/colistin and ampicillin/sulbactam resulted in microbiological clearance in 9 of 14 critically ill patients | Petrosillo et al., |
|
Carbapenem-resistant, colistin-heteroresistant | Rifampicin/colistin and imipenem/colistin were synergistic against heteroresistant isolates and prevented the development of colistin-resistant strains | Rodriguez et al., |
||
Case report | Carbapenem-resistant, colistin-susceptible | Synergistic effect in patients with ventilator-associated pneumonia | Aydemir et al., |
|
Extensively drug-resistant, colistin-susceptible and colistin-resistant | Colistin/fusidic acid and colistin/rifampicin were synergistic in a murine thigh-infection model; The colistin-meropenem combination was also effective when the colistin MIC is ≤32 mg/L. | Fan et al., |
||
Colistin-resistant | The most effective combinations were colistin-rifampin and colistin-teicoplanin; both combinations showed synergistic effect against 8 of 9 colistin-resistant strains | Bae et al., |
||
Colistin+teicoplanin | Multidrug-resistant, colistin-susceptible | Synergistic effect of colistin/daptomycin and colistin/teicoplanin in a mouse model | Cirioni et al., |
|
Multidrug-resistant, colistin-susceptible | Significant synergy | Wareham et al., |
||
Colistin-resistant | The most effective combinations were colistin-rifampin and colistin-teicoplanin; both combinations showed synergistic effect against 8 of 9 colistin-resistant strains | Bae et al., |
||
Colistin+daptomycin | Multidrug-resistant, colistin-susceptible | Synergistic effect of colistin/daptomycin and colistin/teicoplanin in a mouse model | Cirioni et al., |
|
Extensively drug-resistant | The daptomycin-colistin combination was the most effective; the colistin/imipenem combination was also effective | Cordoba et al., |
||
Colistin+vancomycin | Multidrug-resistant, colistin-susceptible | Highly active both in vitro and in an animal model of |
Hornsey and Wareham, |
|
Colistin+fosfomycin | Carbapenem-resistant, colistin-susceptible | Good synergy; no synergy between colistin and sulbactam, colistin and imipenem | Santimaleeworagun et al., |
|
Colistin+fusidic acid | Carbapenem-resistant, colistin-susceptible and colistin-resistant | Bowler et al., |
||
Carbapenem-resistant, colistin-susceptible and colistin-resistant | Robust synergy between fusidic acid and colistin against multidrug-resistant clinical strains, including some colistin-resistant strains | Phee et al., |
||
Extensively drug-resistant, colistin-susceptible and colistin-resistant | Colistin/fusidic acid and colistin/rifampicin were synergistic in a murine thigh-infection model; The colistin-meropenem combination was also effective when the colistin MIC is ≤32 mg/L. | Fan et al., |
||
Colistin+amikacin | Case report | Multidrug-resistant, colistin-susceptible | Successful clinical and microbiological outcomes | Fulnecky et al., |
Colistin+trimethoprim-sulfamethoxazole | Carbapenem-resistant | Colistin/trimethoprim-sulfamethoxazole killed effectively all carbapenem-resistant strains | Nepka et al., |
|
Polymyxin B+netropsin | Colistin-resistant | The survival of infected |
Chung et al., |
|
Trimethoprim-sulfamethoxazole | Carbapenem-resistant | Trimethoprim-sulfamethoxazole killed effectively all carbapenem-resistant strains | Nepka et al., |
|
Novobiocin | Carbapenem-susceptible | Inhibition of frequency of the occurrence of rifampin resistance mutants | Jara et al., |
|
Bacteriophages | Carbapenem-resistant, carbapenem-susceptible | Strong lytic activities and the improvement of survival rates | Jeon et al., |
|
Endolysin (LysABP-01)+colistin | Multidrug-resistant | Synergistic activity | Thummeepak et al., |
|
Artilysins | Carbapenem-resistant, carbapenem-susceptible | Artilysins are effective |
Briers et al., |
|
Antimicrobial peptides | Multidrug-resistant | Good antimicrobial activities | Pires et al., |
|
Rose bengal+ carbapenem | Carbapenem-resistant | Imipenem or meropenem with rose bengal showed synergistic effects | Chiu et al., |
|
β-Aminoketone (MD3)+colistin | Colistin-susceptible, colistin-resistant | Synergistic effect targeting to strains with specific colistin resistance mechanisms; synergy against both colistin-susceptible strains and colistin-resistant strains with mutations in |
Martinez-Guitian et al., |
|
Bulgecin A+ carbapenem | Carbapenem-resistant | Synergistic activity | Skalweit and Li, |
|
Farnesol+colistin | Colistin-resistant | Farnesol increased sensitivity to colistin for colistin-resistant strains | Kostoulias et al., |
|
Oleanolic acid+gentamicin or kanamycin | Carbapenem-susceptible | Synergistic activity | Shin and Park, |
|
Cyanide 3-chlorophenylhydrazone (CCCP)+colistin | Colistin-resistant | CCCP reversed colistin resistance and inhibited the regrowth of the resistant subpopulation | Ni et al., |
|
Colistin-resistant | Synergistic activity | Park and Ko, |
||
ABEPI1 or ABEPI2+minocycline | Carbapenem-susceptible | Synergistic activity | Blanchard et al., |
|
Gallium nitrate | Multidrug-resistant | Good antimicrobial activities; protection of |
Antunes et al., |
|
Gallium protoporphyrin IX | Multidrug-resistant | Good antimicrobial activities | Arivett et al., |
|
Gallium nitrate+colistin | Multidrug-resistant | Good antimicrobial activities; protection of |
Antunes et al., |
|
D-amino acids | Carbapenem-susceptible | Some D-amino acids (D-histidine and D-cysteine) can inhibit bacterial growth, biofilm formation and adherence to eukaryotic cells | Rumbo et al., |
|
Multidrug-resistant | Protection against fatal intestinal infection in a murine infection model | Asahara et al., |
||
Clarithromycin | Multidrug-resistant | Inhibition of bacterial growth and biofilm formation; immunomodulator | Konstantinidis et al., |
|
Lysophosphatidylcholine+carbapenem | Multidrug-resistant strain | Lysophosphatidylcholine in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance from the spleen and lungs and reduced bacteremia and mouse mortality rates | Parra Millan et al., |
|
Lysophosphatidylcholine+tigecycline | Multidrug-resistant strain | Lysophosphatidylcholine in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance from the spleen and lungs and reduced bacteremia and mouse mortality rates | Parra Millan et al., |
|
Lysophosphatidylcholine+colistin | Multidrug-resistant strain | Lysophosphatidylcholine in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance from the spleen and lungs and reduced bacteremia and mouse mortality rates | Parra Millan et al., |
Carbapenems, including imipenem, meropenem, and doripenem, have generally been considered the agents to treat
Sulbactam is a β-lactamase inhibitor and also has affinity for penicillin-binding proteins of
Minocycline, is a broad-spectrum tetracycline antibiotic that has been proposed for treating drug-resistant
Tigecycline is the first glycylcycline class antibiotic that exhibits bacteriostatic activity by binding to the 30S ribosomal subunit, and is active against
Polymyxins are a group of polycationic peptide antibiotics that were discovered more than 60 years ago and exhibit potent efficacy against most Gram-negative bacteria (Liu Q. et al.,
Unfortunately, the emergence of colistin-resistant
A urinary tract
Unlike colistin, polymyxin B is not converted from a prodrug form into an active form; thus, plasma concentrations of polymyxin B more quickly reach target levels (Sandri et al.,
Trimethoprim-sulfamethoxazole is a two antibiotics combination that exerts a synergistic effect by inhibiting successive steps in the folate synthesis pathway against a number of bacteria (Wormser et al.,
The inducible DNA damage response in
The worldwide spread of MDR pathogens has renewed interest in the therapy using bacteriophage, which is a virus that infects and lyses bacteria. Various lytic
An
Bulgecin A is a natural product of
Cyanide 3-chlorophenylhydrazone (CCCP) is an efflux pump inhibitor that decreases the MIC of colistin in colistin-susceptible and colistin-resistant
Gallium is a semi-metallic element in group 13 of the periodic table that binds to biological complexes containing Fe3+ and disrupts essential redox-driven biological processes (Bernstein,
Probiotics are “live microorganisms that confer a health benefit on the host when administered in adequate amounts” (Reid et al.,
The number of studies about
Recent interest about
Various trials to identify a novel alternative to carbapenem or colistin have been performed. Among them, engineered endolysins (artilysins) are particularly interesting, despite evident defects. A lytic enzyme degrading peptidoglycan of bacteria is a promising novel class of antimicrobial agents due to its unique mode of action. Similar to β-lactam antibiotics that are one of the most successful antibiotics, inhibition of peptidoglycan synthesis is a promising target of antimicrobial agents. Because lytic enzymes directly degrade peptidoglycans, but not proteins, the possibility of the emergence of a resistance mechanism is relatively low. In addition, enzymes with relatively high molecular weight are not inhibited by efflux pumps. If the short stability of artilysin in serum and high cost in its production compared with small molecules can be resolved, the improved artilysin can be a good treatment option for carbapenem- or colistin-resistant
CL, JL, MP, and SL contributed to the conception and the design of the review and CL, JL, MP, KP, IB, YK, CC, BJ, and SL researched and wrote the review.
This review was supported by the Cooperative Research Program for Agriculture Science and Technology Development (No. PJ01103103) of Rural Development Administration in Republic of Korea; the Environmental Health Action Program (No. 2016001350004) funded by the Ministry of Environment (MOE) in Republic of Korea; and the National Research Foundation of the Ministry of Education, Republic of Korea (NRF-2015R1C1A1A02037470).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.