Peptide makes drug-resistant bacteria sensitive to antibiotics again
Peptide also kills multidrug-resistant bacteria on its own

Date:
August 6, 2020
Source:
Nanyang Technological University
Summary:
Scientists have developed a synthetic peptide that can make
multidrug- resistant bacteria sensitive to antibiotics again
when used together with traditional antibiotics, offering hope
for the prospect of a combination treatment strategy to tackle
certain antibiotic-tolerant infections. On its own, the synthetic
antimicrobial peptide can also kill bacteria that have grown
resistant to antibiotics.



FULL STORY ========================================================================== Scientists at Nanyang Technological University, Singapore (NTU Singapore)
have developed a synthetic peptide that can make multidrug-resistant
bacteria sensitive to antibiotics again when used together with
traditional antibiotics, offering hope for the prospect of a combination treatment strategy to tackle certain antibiotic-tolerant infections.


==========================================================================
On its own, the synthetic antimicrobial peptide can also kill bacteria
that have grown resistant to antibiotics.

Every year, an estimated 700,000 people globally die of
antibiotic-resistant diseases, according to the World Health
Organisation. In the absence of new therapeutics, infections caused by resistant superbugs could kill an additional 10 million people each year worldwide by 2050, surpassing cancer. Antibiotic resistance arises in
bacteria when they can recognise and prevent drugs that would otherwise
kill them, from passing through their cell wall.

This threat is accelerated by the developing COVID-19 pandemic, with
patients admitted to hospitals often receiving antibiotics to keep
secondary bacterial infections in check, amplifying the opportunity for resistant pathogens to emerge and spread.

The NTU Singapore team, led by Associate Professor Kimberly Kline and
Professor Mary Chan, developed an antimicrobial peptide known as CSM5-K5 comprising repeated units of chitosan, a sugar found in crustacean
shells that bears structural resemblance to the bacterial cell wall,
and repeated units of the amino acid lysine.

The scientists believe that chitosan's structural similarity to the
bacterial cell wall helps the peptide interact with and embed itself
in it, causing defects in the wall and membrane that eventually kill
the bacteria.



==========================================================================
The team tested the peptide on biofilms, which are slimy coats of bacteria
that can cling onto surfaces such as living tissues or medical devices
in hospitals, and which are difficult for traditional antibiotics to
penetrate.

In both preformed biofilms in the lab and biofilms formed on wounds
in mice, the NTU-developed peptide killed at least 90 per cent of the
bacteria strains in four to five hours.

In separate experiments, when CSM5-K5 was used with antibiotics that
the bacteria are otherwise resistant to, more bacteria was killed
off as compared to when CSM5-K5 was used alone, suggesting that the
peptide rendered the bacteria susceptible to antibiotics. The amount of antibiotics used in this combination therapy was also at a concentration
lower than what is commonly prescribed.

The findings were published in the scientific journal ACS Infectious
Diseases in May.

Assoc Prof Kimberly Kline, a Principal Investigator at the Singapore
Centre for Environmental Life Sciences Engineering (SCELSE) at NTU,
said: "Our findings show that our antimicrobial peptide is effective
whether used alone or in combination with conventional antibiotics to
fight multidrug-resistant bacteria. Its potency increases when used with antibiotics, restoring the bacteria's sensitivity to drugs again. More importantly, we found that the bacteria we tested developed little to
no resistance against our peptide, making it an effective and feasible
addition to antibiotics as a viable combination treatment strategy
as the world grapples with rising antibiotic resistance." Prof Mary
Chan, director of NTU's Centre of Antimicrobial Bioengineering, said:
"While efforts are focussed on dealing with the COVID-19 pandemic,
we should also remember that antibiotic resistance continues to be a
growing problem, where secondary bacterial infections that develop in
patients could complicate matters, posing a threat in the healthcare
settings. For instance, viral respiratory infections could allow bacteria
to enter the lungs more easily, leading to bacterial pneumonia, which
is commonly associated with COVID-19."


==========================================================================
How the antimicrobial peptide works Antimicrobial peptides, which
carry a positive electric charge, typically work by binding to the negatively-charged bacterial membranes, disrupting the membrane and
causing the bacteria to die eventually. The more positively charged a
peptide is, the more efficient it is in binding to bacteria and thus
killing them.

However, the peptide's toxicity to the host also increases in line with
the peptide's positive charge -- it damages the host organism's cells
as it kills bacteria. As a result, engineered antimicrobial peptides to
date have met with limited success, said Assoc Prof Kline, who is also
from the NTU School of Biological Sciences.

The peptide designed by the NTU team, called CSM5-K5, is able to
cluster together to form nanoparticles when it is applied to bacteria
biofilms. This clustering results in a more concentrated disruptive
effect on the bacterial cell wall when compared to the activity of
single chains of peptides, meaning it has high antibacterial activity
but without causing undue damage to healthy cells.

To examine CSM5-K5's efficacy on its own, the NTU scientists developed
separate biofilms comprising methicillin-resistant Staphylococcus aureus, commonly known as the MRSA superbug; a highly virulent multidrug-resistant strain of Escherichia coli (MDR E. Coli); and vancomycin-resistant
Enterococcus faecalis (VRE). MRSA and VRE are classified as serious
threats by the US Centers for Disease Control and Prevention.

In lab experiments, CSM5-K5 killed more than 99 per cent of the biofilm bacteria after four hours of treatment. In infected wounds on mice,
the NTU- developed antimicrobial peptide killed more than 90 per cent
of the bacteria.

When CSM5-K5 was used with conventional antibiotics, the NTU team found
that the combination approach led to a further reduction in the bacteria
in both lab-formed biofilms and infected wounds in mice as compared
to when only CSM5- K5 was used, suggesting that the antimicrobial
peptide made the bacteria sensitive to the drugs they would otherwise
be resistant to.

More importantly, the NTU team found that the three strains of bacteria
studied (MRSA, VRE and MDR E. coli) developed little to no resistance
against CSM5-K5.

While MRSA developed low-level resistance against CSM5-K5, this made
MRSA more sensitive to the drug it is otherwise resistant to.

Prof Chan said: "Developing new drugs alone is no longer sufficient to
fight difficult-to-treat bacterial infections, as bacteria continue to
evolve and outsmart antibiotics/ It is important to look at innovative
ways to tackle difficult-to-treat bacterial infections associated with antibiotic resistance and biofilms, such as tackling the bacteria's
defence mechanisms. A more effective and economic method to fight
bacteria is through a combination therapy approach like ours." The next
step forward for the team is to explore how such a combination therapy
approach can be used for rare diseases or for wound dressing.

The research on the CSM5-K5 antimicrobial peptide was funded by NTU,
the National Research Foundation, the Ministry of Education, and the
Ministry of Health.


========================================================================== Story Source: Materials provided by
Nanyang_Technological_University. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Kishore R. V. Thappeta, Yogesh S. Vikhe, Adeline M. H. Yong, Mary B.

Chan-Park, Kimberly A. Kline. Combined Efficacy of an Antimicrobial
Cationic Peptide Polymer with Conventional Antibiotics to Combat
Multidrug-Resistant Pathogens. ACS Infectious Diseases, 2020; 6
(5): 1228 DOI: 10.1021/acsinfecdis.0c00016 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200806101806.htm

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