1. The Antibiotic Cefiderocol
By: Caroline De Groote, Nohemi Dominguez, and Carson Hilton

2. Review of Gram Positive and Gram-Negative Bacteria
In the figure to the left, gram-positive bacteria (GPB) have a second peptidoglycan cell wall that is thick in its structural integrity. Gram-negative bacteria (GNB) have a much thinner cell wall.
GPB only have one cell membrane with a thick cell wall covering it. 
GNB have an outer cell membrane which GPB does not. 
The outer cell membrane on GNB have porins and polysaccharides or lipopolysaccharides. 
“Why Is It More Difficult to Treat Gram Negative Bacteria.” MediMoon, April 30, why-is-it-more-difficult-to-treat-gram-negative-bacteria/.
Review of Gram Positive and Gram-Negative Bacteria

3. Gram Negative Bacteria’s outer membrane make them harder to treat.
Porins and lipopolysaccharides make entry into GNB difficult.
Porins prevent entry of harmful compounds, such as antibiotics. Porins are not just good at keeping things out they also are efficient in expelling harmful compounds already inside the GNB.
Lipopolysaccarides are endotoxins that can detects and protect the GNB from immune attack mechanisms. 
“Why Is It More Difficult to Treat Gram Negative Bacteria.” MediMoon, April 30, is-it-more-difficult-to-treat-gram-negative-bacteria/.

4. Cefiderocol is Effective in Treating Gram Negative Bacteria
Bacteria uses Iron in many different metabolic processes or growth. Iron is not readily available for bacteria so therefore it must absorb iron from the environment.
What Cefiderocol does is use this iron absorption mechanism to enter the GNB (right figure). 
Catechols are 1,2 – dehydrobenzene molecules that bind to iron using their hydroxide groups (left figure). 
Cefiderocol binds to the iron (using a catechol) and is actively transported into the bacteria through the iron transport protein. 
Catechols binding Iron
Cefiderocol
Tillotson, Glenn S. “Trojan Horse Antibiotics–A Novel Way to Circumvent Gram-Negative Bacterial Resistance?” Infectious Diseases: Research and Treatment 9 (January 2016): IDRT.S

5. Structure of Cefiderocol
This catechol binds to Iron via the –OH group making for easier entry into the GNB.
Structure of Cefiderocol
Pubchem. “Cefiderocol.” Accessed March 11,
“What You Should Know About Six Emerging Antibiotics For Diabetic Foot Infections.” Podiatry Today. Accessed March 11,
Cefiderocol is part of an antibiotic class known as the siderophore cephalosporins.
Once Cefiderocol has passed the membranes of GNB, it is free to act in the same way regular antibiotics do to destroy the cell

6. Antibiotics have become less effective because GNB can quickly build resistance to antibiotics. The three ways this resistance is built is through GNB’s two highly selective membranes, porin channels, and the efflux pumps which expel toxins and drugs from the bacteria. 
Porins can adapt and prevent dangerous compounds like antibiotics from entering the bacteria. 
Cefiderocol overcomes these three mechanisms by entering the bacteria through the iron channels, avoiding the porin channels completely. By effectively entering the bacteria, efflux pumps become overwhelmed by trying to expel Cefiderocol. 
Cefiderocol is still in clinical trials so there are no calculated LD50 and ED50. Due to the similarities of cefiderocol with other antibiotics, such as the beta-lactam ring, doses should be similar to antibiotics that are already in use. 
“New Investigational Antibiotic Effective against Drug-Resistant Bacteria in Phase 2 Trial.” ScienceDaily. Accessed March 11,
Three antibiotic resistance mechanisms Cefiderocol overcomes in gram-negative bacteria.

7. Pros and Cons
Pros
Cons
Dr Portsmouth says: "Cefiderocol was found to be both safe and tolerable in a population of older patients who were very ill with complex comorbid conditions and a wide range of multidrug- resistant pathogens. Our results support cefiderocol as a novel approach that might be used to overcome Gram-negative resistance.“
Adverse effects: rash, a blood thyroid-stimulating hormone level increase, pyrexia, increase in aspartate aminotransferase level, increase in alanine aminotransferase level, blood in the urine, headache, blood urea level increase and decrease in blood thyroid-stimulating hormone level
Eventually resistance will be build against Cefiderocol
Works efficiently against known resistant mechanisms in bacteria
Still in clinical trials with possible unknown adverse effects
Work well against important multi drug resistant pathogenic bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.
Katsube, Takayuki, Roger Echols, Juan Camilo Arjona Ferreira, Heidi K. Krenz, Jolene Kay Berg, and Christopher Galloway. “Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment: Journal of Clinical Pharmacology.” The Journal of Clinical Pharmacology 57, no. 5 (May 2017): 584–91.
“New Investigational Antibiotic Effective against Drug-Resistant Bacteria in Phase 2 Trial.” ScienceDaily. Accessed March 11,
“What You Should Know About Six Emerging Antibiotics For Diabetic Foot Infections.” Podiatry Today. Accessed March 11,