Combinations of polymyxins with one or two other antibiotics (doripenem or meropenem, rifampicin, tigecycline, fosfomycin, vancomycin, or teicoplanin) have been used to circumvent resistance mechanisms. Analogs of polymyxins have entered preclinical work or clinical trials as antibiotics. For example, QPex Biopharma developed a polymyxin, QPX9003, in which the alkanoyl chain is replaced by a 2,4-dichlorobenzoyl moiety 127 with improved antibacterial activity and reduced nephrotoxicity; the compound showed appropriate toxicity, pharmacokinetic, and pharmacodynamic data from Phase 1 studies. 128 Spero Therapeutics developed N-aryl analogs of polymyxin B, developing the compound SPR206 which entered phase 1 clinical trials. MicuRx Pharmaceuticals developed a lactone-containing analog of polymyxin, MRX8, which showed antibacterial activity against Gram-negative bacteria, including carbapenem-resistant Acinetobacter baumanii 130 ; the compound is in Phase 1 clinical trials in the US. Northern Antibiotics in Finland developed the polymyxins NAB739 and NAB815 and found them to be more effective against pyelonephritis in mice than polymyxin B 132 ; a related polymyxin analog, NAB741, entered Phase 1 clinical trials in 2017. Chloramphenicol and Analogs (Amphenicols): Chloramphenicol is an antibiotic isolated from Streptomyces venezuelae in 1948 134 and approved by the US FDA in 1949. It is a broadspectrum antibiotic, inhibiting the growth of Gram-negative aerobic (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitides and gonorrhea, Brucella species, and Bordetella pertussis) and Gram-positive and -negative anaerobic bacteria (cocci, Clostridium, and Bacillus fragilis); most Escherichia coli and Klebsiella pneumoniae are also susceptible to chloramphenicol. It is thus used for treating typhoid fever, bacterial meningitis, anaerobic bacterial infections, and rickettsial and mycoplasmic infections in susceptible strains or when other antibiotics are ineffective. Chloramphenicol binds to the 50S subunit of the bacterial ribosome at the peptidyltransferase center (PTC), inhibiting protein synthesis. Chloramphenicol, however, leads to dose-related reversible anemia, leucopenia, and thrombosis and also to an irreversible aplastic anemia which (while uncommon) is often fatal; analogs lacking the nitro group show dose-dependent reversible blood cell suppression but do not cause aplastic anemia. The toxicity of chloramphenicol and its analogs is attributed to its damage to mitochondria via suppression of mitochondrial protein synthesis. Chloramphenicol is also associated with "grey baby syndrome", cyanosis, and low blood pressure in neonates caused by the lack of livermediated metabolism of chloramphenicol. As a result, chloramphenicol is no longer approved for human use in the US. Chloramphenicol succinate was developed as a prodrug of chloramphenicol and approved by the US FDA but is no longer available; it has similar toxicity to chloramphenicol. Thiamphenicol and florfenicol replace the nitro group of chloramphenicol with a methylsulfonylgroup, with a fluoro moiety replacing the hydroxyl group of chloramphenicol; while neither cause irreversible aplastic anemia, they still cause reversible bone marrow suppression, deprecating their use. Further analogs of chloramphenicol have been studied to attempt to provide novel and useful antibiotics with reduced side effects. For example, the replacement of the chloramphenicol primary alcohol with an L-lysine amide yields a compound that bound strongly to the ribosome and inhibited puromycin effects on the ribosome, an inhibition characteristic of binding to the ribosome A-site. 141