Achaogen’s Role in Antibiotic Development and Research

Achaogen was a biopharmaceutical company dedicated to developing novel antibiotics, particularly for infections caused by multidrug-resistant bacteria. With antimicrobial resistance posing a serious global health threat, their work aimed to address gaps in treatment where existing drugs were failing.

Focus on Gram-Negative Bacterial Infections

Gram-negative bacterial infections present a major challenge due to their intrinsic resistance mechanisms and ability to rapidly acquire new defenses. Unlike gram-positive bacteria, which have a thick peptidoglycan layer accessible to many antibiotics, gram-negative bacteria possess an outer membrane rich in lipopolysaccharides. This barrier restricts drug penetration, making treatment more difficult. Efflux pumps expel antibiotics from the bacterial cell, and beta-lactamases degrade beta-lactam antibiotics, further limiting therapeutic options. These factors contribute to the persistence of pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, which frequently cause hospital-acquired infections and sepsis.

The World Health Organization (WHO) classifies carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas aeruginosa as priority pathogens requiring new treatment strategies. Achaogen focused on developing antibiotics that could overcome these resistance mechanisms, particularly those targeting metallo-beta-lactamases and serine beta-lactamases—enzymes that neutralize many potent antibiotics. CRE infections are especially concerning, with mortality rates exceeding 40% in some cases, highlighting the need for new treatments.

Existing antibiotics often have limited efficacy, even in combination therapies. Polymyxins like colistin have been reintroduced as salvage treatments, but their nephrotoxicity and neurotoxicity restrict use. Tigecycline, a glycylcycline antibiotic, shows activity against some resistant strains but often requires adjunctive therapy. Achaogen aimed to develop agents with improved pharmacokinetics and mechanisms of action that bypass traditional resistance pathways. Their research focused on optimizing drug penetration, inhibiting resistance enzymes, and minimizing toxicity to improve patient outcomes.

Laboratory Methods in Antibiotic Discovery

Developing new antibiotics requires microbiological, biochemical, and pharmacological techniques to ensure efficacy against resistant bacteria. Achaogen employed high-throughput screening, structure-based drug design, and microbiological assays to identify compounds with strong antibacterial potential.

High-throughput screening (HTS) allowed researchers to rapidly evaluate thousands of compounds for antibacterial activity. Automated platforms exposed resistant bacterial strains to diverse chemical libraries, assessing their impact on bacterial growth. While many initial hits lacked specificity or had poor pharmacokinetics, medicinal chemistry refined promising candidates. Structure-based drug design used X-ray crystallography and computational modeling to enhance binding affinity and stability, improving drug-target interactions.

Once lead compounds showed promise, microbiological assays evaluated their spectrum of activity and resistance suppression. Minimum inhibitory concentration (MIC) testing determined the lowest effective concentration, while time-kill studies distinguished bactericidal from bacteriostatic effects. Serial passage experiments assessed the likelihood of resistance development by exposing bacteria to sub-inhibitory antibiotic concentrations over multiple generations. Compounds with a low propensity for resistance were prioritized for further development.

Pharmacokinetic and pharmacodynamic (PK/PD) profiling ensured effective drug concentrations while minimizing toxicity. In vitro models, such as hollow-fiber infection systems, simulated human drug exposure, refining dosing regimens before animal testing. These studies determined optimal drug concentrations, half-life, and tissue penetration in challenging infection sites like the lungs and bloodstream. Metabolic stability assays evaluated how quickly a drug was broken down by liver enzymes, guiding structural modifications to prolong activity.

Portfolio of Investigational Compounds

Achaogen’s research pipeline focused on antibiotics with novel mechanisms of action to combat multidrug-resistant gram-negative pathogens. One of their most notable compounds was plazomicin, a next-generation aminoglycoside designed to evade common resistance mechanisms. Unlike older aminoglycosides such as gentamicin and amikacin, which are often rendered ineffective by bacterial aminoglycoside-modifying enzymes, plazomicin was structurally modified to resist enzymatic degradation. This allowed it to retain potency against CRE, a particularly challenging group of pathogens responsible for severe bloodstream infections and pneumonia. Clinical trials demonstrated plazomicin’s efficacy in treating complicated urinary tract infections (cUTIs), leading to its FDA approval under the brand name Zemdri.

Beyond plazomicin, Achaogen explored additional small-molecule antibiotics aimed at overcoming resistance barriers. Their investigational compounds included inhibitors targeting bacterial ribosomes and enzymes essential for cell wall synthesis, with an emphasis on minimizing cross-resistance with existing therapies. One promising avenue involved beta-lactamase inhibitors that restored the activity of beta-lactam antibiotics against resistant strains. By combining these inhibitors with traditional antibiotics, Achaogen aimed to extend the lifespan of existing drug classes while reducing selective pressure that drives resistance.

The company also investigated dual-target compounds, which disrupt multiple bacterial processes simultaneously, making it harder for pathogens to develop resistance. This strategy was particularly relevant for Pseudomonas aeruginosa and Acinetobacter baumannii, which readily acquire resistance through horizontal gene transfer and efflux pump activation. By leveraging innovative structural modifications and combination therapies, Achaogen sought to develop antibiotics with sustained clinical utility despite evolving bacterial defenses.

Clinical Evaluations in Drug-Resistant Pathogens

Achaogen’s clinical evaluations focused on pathogens with limited or no viable treatment options. Plazomicin, their lead compound, underwent rigorous testing for complicated urinary tract infections (cUTIs) and bloodstream infections caused by CRE. The EPIC (Evaluating Plazomicin in cUTI) study showed higher microbiological eradication rates compared to standard aminoglycosides, reinforcing its potential as a next-generation treatment.

Beyond cUTIs, Achaogen investigated plazomicin for life-threatening bloodstream infections, including those associated with sepsis. The CARE (Combating Antibiotic-Resistant Enterobacterales) study aimed to evaluate its role in treating CRE bloodstream infections, which have exceptionally high mortality rates. While data suggested benefits in certain patient subgroups, the study did not achieve statistical superiority over colistin-based regimens, reflecting the complexity of treating highly resistant infections. These findings contributed to a growing body of evidence supporting alternative strategies, such as combination therapies, to improve outcomes.

Collaborations Across Research Institutions

Achaogen recognized that addressing antibiotic resistance required collaboration across scientific disciplines. To accelerate drug discovery and development, the company partnered with academic institutions, government agencies, and nonprofit organizations. These collaborations provided access to specialized expertise, advanced research methodologies, and critical funding.

One of the most impactful partnerships was with the Biomedical Advanced Research and Development Authority (BARDA), which provided financial and logistical support for plazomicin and other investigational antibiotics. BARDA’s involvement facilitated large-scale clinical trials and helped Achaogen navigate the complex regulatory landscape.

Achaogen also worked with academic research centers specializing in bacterial genomics and structural biology, leveraging technologies such as cryo-electron microscopy and next-generation sequencing to identify novel drug targets. These collaborations extended to global health organizations focused on antimicrobial resistance, ensuring that Achaogen’s research aligned with broader public health initiatives to preserve existing antibiotics while introducing new treatment options.