New antibiotic is capable of killing resistant bacteria – 01/03/2024 – Health

Researchers have discovered a new class of antibiotics capable of killing multidrug-resistant bacteria, a global health problem that concerns health officials.

Antibiotic resistance occurs when strains of microorganisms that previously responded to antimicrobial treatments are no longer susceptible, prolonging infections, causing new hospitalizations and increasing the risk of transmission.

For this reason, the discovery of the new class of drugs with clinical potential brings hope to doctors, health authorities and patients around the world.

The group is part of the so-called MPCs (macrocyclic peptides), molecules larger than most known antibiotics and which show promising antimicrobial activity, including combating multidrug-resistant strains.

In a database with around 45 thousand molecules, scientists found the new substance, called zosurabalpine (zosurabalpin, in English), and described for the first time in an article in this Wednesday’s edition (3) of Nature magazine by Claudia Zampaloni, Patrizio Mattei, Konrad Bleicher and other colleagues from the pharmaceutical company Roche Group (Switzerland) and Harvard University (USA), among others.

The group of antibiotics has action against gram-negative and gram-positive bacteria, but zosurabalpine was effective mainly against CRAB (Acinetobacter baumannii carbapenem-resistant). The drug was tested in laboratory dishes infected with the bacteria and in mice, where it managed to inhibit bacterial growth.

A A. baumannii is a gram-negative bacterium listed among the highest priority microorganisms by the WHO (World Health Organization) due to antimicrobial resistance. According to a study published in the journal The Lancet, approximately 1.3 million deaths per year worldwide are caused by resistant bacteria.

The discovery is, therefore, a milestone for the development and research of new drugs capable of combating microorganisms. “It has been more than 50 years since the last class of antibiotics capable of treating infections caused by gram-negative bacteria was launched, and there is now resistance to drugs from virtually all existing classes. Any new class of antibiotics that has the ability to treat infections caused by resistant bacteria, such as CRAB, is a significant advance,” he told Sheet Kenneth Bradley, corresponding author of the study and global head of infectious disease discovery at Roche.

In the study, the authors state that new antibiotics described in recent years are, for the most part, derived from existing substances, and that finding new classes of drugs is extremely rare.

In a complementary study also published this Wednesday (3) in Nature, Daniel Kahne and colleagues from Harvard University describe the substance’s mechanism of action.

It works like this: the bacteria A. baumannii resistant has several lipopolysaccharide (LPS) molecules in the outer membrane that prevent the antibiotic from penetrating the cell. Think of it as a protective film. Experts found two ways to prevent this protection: block the synthesis of LPS or interrupt its transport to the outer membrane, thus preventing the formation of the film, making the bacteria susceptible again to some antibiotics. The new drug acts in the second way.

By binding to a protein complex (LptB2FGC) between the two layers of the cell membrane (inner and outer), zosurabalpine blocks the LPS transport pathway. These molecules end up accumulating in the internal membrane of the bacteria, preventing other exchanges between the bacteria and the external environment. Without transport, cell death occurs.

A curious fact about zorusabalpine’s mode of action is that it does not interact with the cytoplasm, which makes the acquisition of long-term microbial resistance difficult.

“The outer membrane is important to bacteria because it helps them survive adverse conditions and resist immune defense mechanisms. LPS is produced inside the bacterial cell but needs to be transported to the outer membrane, a process carefully controlled by these microorganisms. Without the LPS membrane, bacteria have difficulty establishing infections. Even for rare bacteria that can survive without outer membranes, the transport system is toxic to them, leading to their death,” Bradley said.

As it is highly specific for binding to a protein complex of A. baumanniithe risk of resistant strains emerging through the process of mutation or horizontal transfer — the acquisition of mutated genes from other bacteria to which one is trying to combat — is low.

The study authors conclude that the new molecule overcomes existing drug resistance mechanisms, which currently available antibiotics are unable to overcome.

“With this significant discovery, zosurabalpine has the potential to address a major unmet need in the fight against antimicrobial resistance,” they add.