Editorial

Developing new-generation antibiotics to curb antibiotic resistance

Antimicrobial resistance, or AMR, is a major public health issue. Bacterial diseases we used to successfully treat with antibiotics are re-emerging as serious threats, killing an estimated 700,000 people each year, a number that is predicted to reach 10 million by 2050. If the AMR challenge is not solved by then, the cost associated with it will run into an estimated $100 trillion dollar expenditure.

In the “post-antibiotic era,” multidrug-resistant superbugs can turn into mass killers and compromise other life-saving achievements of modern medicine, including surgery, organ transplantations and cancer chemotherapy.

A list compiled by WHO of priority pathogens that pose the greatest threats to human health includes several families of bacteria that cause critical infections in hospitals settings (Acinetobacter, Pseudomonas and various Enterobacteriaceae), and more common diseases such as food poisoning caused by Salmonella.

Farokh Dotiwala, MBBS, PhD
Farokh Dotiwala

Other diseases were not included in the list because they already represented global priorities that have an especially severe impact on lower income countries. In 2017, 460,000 new cases of multidrug-resistant tuberculosis were registered.

Although selective pressure caused by excessive or inappropriate use of antimicrobials in health care, agriculture and farming has to be blamed for the emergence of AMR, a 30-year void in the discovery of novel classes of antibiotics has left us unprepared to fight back the superbugs.

New rational, out-of-the-box strategies are imperative if we want to solve one of the biggest challenges of our era.

I was recently one of the organizers of the Symposium on Gram-Negative Bacterial Resistance at The Wistar Institute to bring together top experts in the pharmaceutical, biotech, government and academic spheres to share their latest discoveries, concepts and tools to combat AMR.

In my laboratory at The Wistar Institute, we are developing novel immune antibiotics that could target bacteria while also recruiting the immune system to enhance the antimicrobial activity.

Synergy between the host immunity and antibiotics is an important factor in the clearance of antibiotic-resistant bacteria. Poor antigen presentation allows bacteria to evade detection by the adaptive immune system, namely B cells and CD4 and CD8 T cells, to persist longer in the host and thereby have higher chances to develop resistance.

Resistance to vaccines has historically not been an issue. In fact, whereas antimicrobial drugs clear infections by strictly targeting the pathogens, vaccines do so by engaging the immune system, which, in turn, results in multiple, host-specific antibody and/or T cell responses. The multiplicity of pathogen-targeting mechanisms induced by vaccines ensures that, relative to antimicrobial drugs, more mutations are needed to confer resistance to vaccines.

Following this model, our strategy relies on inducing a rapid, local antibacterial immune response that will synergize with the pathogen-killing activity and prevent the onset of resistance.

The innate immune killer cells can recognize pathogen-associated molecular patterns (PAMPs), home in on the invading pathogens and quickly kill them. Because many such PAMPs are essential for normal bacterial growth and virulence, by targeting one or more PAMP pathways in bacteria, our immune antibiotics can simultaneously kill them — exerting direct antibiotic activity — and make them more “visible” to the immune system.

In this double-pronged strategy, inhibitors of the PAMP metabolism would specifically kill multiple bacteria with no toxic effects on the host cells, which do not have these bacterial pathways, while also enhancing innate killer cell activation, resulting in rapid proliferation at the local infection site (within 6 hours).

Activated killer lymphocytes induce “microptosis,” or programmed cell death in microbes, using the pore-forming peptide granulysin to permeabilize microbial membranes and deliver granzymes that cleave a set of bacterial proteins that are critical for survival.

Because chemical inhibitors of specific PAMP pathways are not commercially available, we designed our own compounds for proof-of-concept studies and used computer-aided molecular modeling to screen millions of commercially available compounds for their ability to specifically block the target enzymes. The most promising hits have been validated and further studied with the goal of finding select compounds to move forward to clinical trials.

We confirmed that our prototype inhibitor molecules specifically suppress the growth of gram-negative bacteria. We also established that this inhibition exerts its toxicity by interfering with bacterial respiration and disrupting the bacterial cell wall.

Importantly, these effects were reproduced on clinical isolates of drug-resistant bacteria, confirming the clinical potential of these immune antibiotic compounds.

Finally, our compounds were effective, as postulated, in activating innate killer cells in human peripheral mononucleated cells and in humanized mouse models of infection.

Antimicrobial resistance, or AMR, is a major public health issue. Bacterial diseases we used to successfully treat with antibiotics are re-emerging as serious threats, killing an estimated 700,000 people each year, a number that is predicted to reach 10 million by 2050. If the AMR challenge is not solved by then, the cost associated with it will run into an estimated $100 trillion dollar expenditure.

In the “post-antibiotic era,” multidrug-resistant superbugs can turn into mass killers and compromise other life-saving achievements of modern medicine, including surgery, organ transplantations and cancer chemotherapy.

A list compiled by WHO of priority pathogens that pose the greatest threats to human health includes several families of bacteria that cause critical infections in hospitals settings (Acinetobacter, Pseudomonas and various Enterobacteriaceae), and more common diseases such as food poisoning caused by Salmonella.

Farokh Dotiwala, MBBS, PhD
Farokh Dotiwala

Other diseases were not included in the list because they already represented global priorities that have an especially severe impact on lower income countries. In 2017, 460,000 new cases of multidrug-resistant tuberculosis were registered.

Although selective pressure caused by excessive or inappropriate use of antimicrobials in health care, agriculture and farming has to be blamed for the emergence of AMR, a 30-year void in the discovery of novel classes of antibiotics has left us unprepared to fight back the superbugs.

New rational, out-of-the-box strategies are imperative if we want to solve one of the biggest challenges of our era.

I was recently one of the organizers of the Symposium on Gram-Negative Bacterial Resistance at The Wistar Institute to bring together top experts in the pharmaceutical, biotech, government and academic spheres to share their latest discoveries, concepts and tools to combat AMR.

In my laboratory at The Wistar Institute, we are developing novel immune antibiotics that could target bacteria while also recruiting the immune system to enhance the antimicrobial activity.

Synergy between the host immunity and antibiotics is an important factor in the clearance of antibiotic-resistant bacteria. Poor antigen presentation allows bacteria to evade detection by the adaptive immune system, namely B cells and CD4 and CD8 T cells, to persist longer in the host and thereby have higher chances to develop resistance.

Resistance to vaccines has historically not been an issue. In fact, whereas antimicrobial drugs clear infections by strictly targeting the pathogens, vaccines do so by engaging the immune system, which, in turn, results in multiple, host-specific antibody and/or T cell responses. The multiplicity of pathogen-targeting mechanisms induced by vaccines ensures that, relative to antimicrobial drugs, more mutations are needed to confer resistance to vaccines.

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Following this model, our strategy relies on inducing a rapid, local antibacterial immune response that will synergize with the pathogen-killing activity and prevent the onset of resistance.

The innate immune killer cells can recognize pathogen-associated molecular patterns (PAMPs), home in on the invading pathogens and quickly kill them. Because many such PAMPs are essential for normal bacterial growth and virulence, by targeting one or more PAMP pathways in bacteria, our immune antibiotics can simultaneously kill them — exerting direct antibiotic activity — and make them more “visible” to the immune system.

In this double-pronged strategy, inhibitors of the PAMP metabolism would specifically kill multiple bacteria with no toxic effects on the host cells, which do not have these bacterial pathways, while also enhancing innate killer cell activation, resulting in rapid proliferation at the local infection site (within 6 hours).

Activated killer lymphocytes induce “microptosis,” or programmed cell death in microbes, using the pore-forming peptide granulysin to permeabilize microbial membranes and deliver granzymes that cleave a set of bacterial proteins that are critical for survival.

Because chemical inhibitors of specific PAMP pathways are not commercially available, we designed our own compounds for proof-of-concept studies and used computer-aided molecular modeling to screen millions of commercially available compounds for their ability to specifically block the target enzymes. The most promising hits have been validated and further studied with the goal of finding select compounds to move forward to clinical trials.

We confirmed that our prototype inhibitor molecules specifically suppress the growth of gram-negative bacteria. We also established that this inhibition exerts its toxicity by interfering with bacterial respiration and disrupting the bacterial cell wall.

Importantly, these effects were reproduced on clinical isolates of drug-resistant bacteria, confirming the clinical potential of these immune antibiotic compounds.

Finally, our compounds were effective, as postulated, in activating innate killer cells in human peripheral mononucleated cells and in humanized mouse models of infection.