Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions
Abstract
:1. Introduction
2. Mechanisms of Antimicrobial Resistance in S. aureus
3. Mechanisms of Antimicrobial Resistance in Enterococcus spp.
4. Mechanisms of Antimicrobial Resistance in P. aeruginosa
5. Mechanisms of Antimicrobial Resistance in E. coli
6. Mechanisms of Antimicrobial Resistance in K. pneumoniae
7. Mechanisms of Antimicrobial Resistance in A. baumannii
8. Overcoming Resistance through Novel Antibiotics
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Pathogen | Antibiotic Resistance | Median Number of Infections | Median Number of Attributable Deaths |
---|---|---|---|
E. coli | Third-Generation Cephalosporin * | 297,416 | 9066 |
Carbapenem # | 2619 | 141 | |
Colistin | 7156 | 621 | |
Overall | 307,191 | 9828 | |
S. aureus | Methicillin-resistant (MRSA) | 148,727 | 7049 |
P. aeruginosa | > = 3 antibiotic groups * | 9028 | 572 |
Carbapenem # | 61,892 | 4155 | |
Colistin | 1262 | 84.5 | |
Overall | 72,182 | 4811.5 | |
K. pneumoniae | Third-Generation Cephalosporin * | 68,588 | 3687 |
Carbapenem# | 15,947 | 2118 | |
Colistin | 7450 | 1635 | |
Overall | 91,985 | 7440 | |
Enterococcus spp. | Vancomycin | 16,146 | 1081 |
Acinetobacter spp. | Aminoglycoside and Fluoroquinolone | 2182 | 100 |
Carbapenem # | 27,343 | 2363 | |
Colistin | 1084 | 94.5 | |
Overall | 30,609 | 2557.5 | |
Overall | 666,840 | 32,767 |
Antibiotic Class | S. aureus | Enterococcus spp. |
---|---|---|
Penicillins | Penicillinase, production of PBP2a | Low affinity PBPs |
Cephalosporins 1st gen. | PBP2a | Low affinity PBPs |
Cephalosporins 2nd gen. | PBP2a | Low affinity PBPs |
Cephalosporins 3rd gen. | PBP2a | Low affinity PBPs |
Cephalosporins 4th gen. | PBP2a | Low affinity PBPs |
b-lactamase inhibitors | PBP2a | |
Carbapenems | Development of PBP2a | Low affinity PBPs |
Tetracyclines | Ribosomal methylation of binding sites, efflux pumps | Ribosomal methylation of binding sites, efflux pumps |
Tigecyclines | Efflux pumps | Ribosomal methylation of binding sites, efflux pumps |
Macrolides and clindamycin | Ribosomal methylation of binding sites, efflux pumps | Efflux pumps, clindamycin inactivating enzymes |
Fluoroquinolones | Mutations in topoisomerase IV and DNA gyrase, efflux pumps | Mutations in topoisomerase IV and DNA gyrase, production of protection proteins |
Rifampicin | Mutations in RNA polymerase gene | Mutations in RNA polymerase gene |
TMP/SMX | Mutations in DHPS and DHFR | Folate absorption from environment |
Aminoglycosides | Aminoglycoside degradation enzymes | Aminoglycoside degradation enzymes, ribosomal mutations |
Daptomycin | Electrostatic repulsion through increase to the cell-surface charge | E faeccium: electrostatic repulsion through increase to the cell-surface charge. E. faecalis: redistribution of cardiolipin away from septum plane |
Vancomycin | VRSA: altered structure of peptidoglycan precursors from D-Ala-D-Ala to D-Ala-D-Lac; VISA: increased production of peptidoglycan, thicker cell wall, decoy D-Ala-D-Ala dipeptides on cell surface | Altered structure of peptidoglycan precursors from D-Ala-D-Ala to D-Ala-D-Lac |
Linezolid | Mutations to the 23S rRNA, altering required modifications to the 23S rRNA, mutations to the 50S ribosomal L3 protein | Mutations to the 23S rRNA |
Antibiotic Class | P. auruginosa | E. coli | K. pneumoniae | A. baumanii |
---|---|---|---|---|
Penicillins | AmpC, ESBLs, other b-lactamases | AmpC, ESBLs, other b-lactamases | AmpC, ESBLs, other b-lactamases | AmpC, ESBLs, other b-lactamases |
Cephalosporins 1st gen. | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs |
Cephalosporins 2nd gen. | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs |
Cephalosporins 3rd gen. | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs | AmpC, ESBLs |
Cephalosporins 4th gen. | ESBLs | ESBLs | ESBLs | ESBLs |
b-lactamase inhibitors | AmpC | AmpC | AmpC | AmpC |
Aztreonam | ESBLs | ESBLs | ESBLs | ESBLs |
Carbapenems | Class B & D carbapenemases | Class A, B & D carbapenemases | Class A, B & D carbapenemases | Class B & D carbapenemases |
Tetracyclines | Efflux pumps | Efflux pumps | Efflux pumps | Efflux pumps |
Tigecycline | Efflux pumps | Efflux pumps, porin downregulation | acrAB efflux pump | AdeABC efflux pump, reduced membrane permeability |
Macrolides and clindamycin | Efflux pumps | Efflux pumps, macrolide inactivating enzymes, target site modification | ||
Fluoroquinolones | Mutations in topoisomerase IV and DNA gyrase genes, efflux pumps | Mutations in DNA gyrase gene | Mutations in DNA gyrase gene, efflux pumps, enzyme protection proteins, fluoroquinolone degradation enzymes | Mutations in genes for DNA gyrase and topoisomerase IV, efflux pumps, enzyme protection proteins, fluoroquinolone degradation enzymes |
Rifampicin | Mutations in RNA polymerase gene | Mutations in RNA polymerase gene | Enzymatic degradation | Mutations in RNA polymerase gene, efflux pumps, enzymatic degradation |
TMP/SMX | Efflux pumps | Overproduction of DHFR, mutation of DHPS | ||
Aminoglycosides | Aminoglycoside degradation enzymes, efflux pumps | Aminoglycoside degradation enzymes | Aminoglycoside degradation enzymes, production of 16SrRNA | Aminoglycoside degradation enzymes |
Colistin | Reduction of membrane negative charge through addition of N4-aminoarabinose to lipid A | Reduction of membrane negative charge through addition of phosphoethanolamine to lipid A | Reduction of membrane negative charge through addition of phosphoethanolamine to lipid A | efflux pumps, loss of LPS production, alterations in the structure of lipid A |
Antibiotic | Resistance Mechanisms Designed to Overcome | Active Against | Inactive Against | Indications |
---|---|---|---|---|
Cephalosporins | ||||
Ceftobiprole | Active against altered PBPs, such as PBP2a and PBP2x | MRSA, VRSA, PRSP, Gram-negative bacteria | ESBLs, AmpC, Class A, B and D carbapenemases | CAP, SSTI |
Ceftaroline | Active against altered PBPs, such as PBP2a | MRSA | ESBLs, AmpC, Class A, B and D carbapenemases | CAP, SSTI |
Cefiderocol | Utilizes iron to bypass porins, accumulates in periplasmic space. Resistant to hydrolysis to all β-lactamases: ESBLs, AmpC, Class A, B and D carbapenemases | MDR Gram-negative bacteria | - | HAP, VAP, cUTI |
Ceftolozane-tazobactam | Ceftolozane overcomes P. aeuruginosa resistance mechanisms: efflux pumps, altered PBPs and porins. Tazobactam confers resistance to ESBLs | MDR P. aeuruginosa | cUTI, cIAI | |
Novel β-lactam inhibitor combination | ||||
Meropenem-vaborbactam | Vaborbactam inhibits ESBLs, Class C cephalosporinases and Class A carbapenemases | MDR Gram-negative bacteria | Class B carbapenemases | HAP, VAP, cUTI, cIAI |
Imipenem-relebactam | Relebactam inhibits ESBLs, Class C cephalosporinases and Class A carbapenemases | MDR Gram-negative bacteria | Class B and D carbapenemases | |
Aztreonam-avibactam | Avibactam inhibits all Class A and Class C, and some Class D β-lactamases. Aztreonam inhibits Class B β-lactamases. | MDR Gram-negative bacteria | - | Approval pending |
Ceftazidime-avibactam | Avibactam inhibits all Class A and Class C, and some Class D β-lactamases. | MDR Gram-negative bacteria | Class B carbapenemases | HAP, VAP, cUTI, cIAI |
Fluoroquinolones | ||||
Delafloxacin | Balanced inhibition of topoisomerase IV and DNA gyrase, decreasing resistance potential. Enhanced penetration and activity in acidic environments, such as infection sites | Fluoroquinolone-resistant S. aureus, Gram-negative bacteria | CAP, SSTI | |
Tetracyclines | ||||
Omadacycline | Active against tetracycline efflux pumps or ribosomal protection proteins | MRSA, VRE, PRSP, Gram-negative bacteria | P. aeruginosa | CAP, SSTI |
Eravacycline | Active against bacteria that have efflux pumps or ribosomal protection proteins | MDR Acinetobacter spp., ESBL-producing Enterobacteriaceae, VRE, MRSA and S. pneumoniae | cIAI | |
Aminoglycoside | ||||
Plazomicin | Resistant to degradation by aminoglycoside nucleotidyltransferases, phosphotransferases and acetyltransferases | Gram-negative bacteria that produce aminoglycoside degradation enzymes | 16SrRNA methylase producing bacteria | cUTI |
Lipoglycopeptides | ||||
Dalbavancin | Increased membrane anchoring | MRSA, VISA and VRE exhibiting the VanB phenotype | VRSA and VRE exhibiting the VanA phenotype | SSTI |
Telavancin | Increased membrane anchoring, disruption of membrane integrity, permeability and potential | MRSA, VISA and VRE exhibiting the VanB phenotype | VRSA and VRE exhibiting the VanA phenotype | SSTI, HAP & VAP by S. aureus |
Oritavancin | Increased membrane anchoring, disruption of membrane integrity, permeability and potential, RNA synthesis inhibition, binding to both D-Ala-D-Ala & D-Ala-D-Lac dipeptides | MRSA, VISA & VRE with VanB phenotype, VRSA & VRE with VanA phenotype | - | SSTI |
Oxazolidinone | ||||
Tedizolid | More potent binding to the 23S rRNA binding site than linezolid | VRE, MRSA and linezolid-resistant isolates | - | SSTI |
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Kakoullis, L.; Papachristodoulou, E.; Chra, P.; Panos, G. Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions. Antibiotics 2021, 10, 415. https://doi.org/10.3390/antibiotics10040415
Kakoullis L, Papachristodoulou E, Chra P, Panos G. Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions. Antibiotics. 2021; 10(4):415. https://doi.org/10.3390/antibiotics10040415
Chicago/Turabian StyleKakoullis, Loukas, Eleni Papachristodoulou, Paraskevi Chra, and George Panos. 2021. "Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions" Antibiotics 10, no. 4: 415. https://doi.org/10.3390/antibiotics10040415