Gram-negative-only antibiotics need to be developed to reduce antibiotic resistance and minimize adverse effects on the gut microbiome. Currently, colistin is the only FDA-approved Gram-negative-only antibiotic but is known to cause nephrotoxicity in 60% of patients and is exclusively used as a last resort for the treatment of multidrug-resistant infections. Consequently, broad-spectrum agents are used to treat Gram-negative infections which leads to significant perturbation of the microbiome, increasing the vulnerability to colonization of opportunistic pathogens, like C. difficile, as well as increasing risk for gastrointestinal, renal, and hematological abnormalities. When coupled with the appropriate diagnostics for determining the infection-causing pathogen, Gram-negative-only antibiotics can mitigate disruption to commensal bacteria and reduce susceptibility to the development of subsequent diseases resulting from changes in the gut microbiota. An underexplored cellular target for developing Gram-negative-only antibiotics is the LolCDE complex, a three-part protein system responsible for lipoprotein transport across the inner and outer membranes in Gram-negative bacteria.